Melanin modification compositions and methods of use

ABSTRACT

A method for the modification of melanin distribution, and the composition thereof to modify melanin distribution are disclosed. A method for the reduction of melanin distribution, and the composition thereof to reduce melanin distribution are disclosed. A representative composition comprises 4-ethoxybenzaldehyde and one or more additional active agents as well as a pharmaceutically acceptable carrier or excipient. Carriers and excipients may be formulated for topical administration. Compositions may also be formulated for transdermal administration. The compositions may be used for the prevention and treatment of pigmentation disorders, by way of non-limited example, post-inflammatory hyperpigmentation and others. The compositions may be used for lightening skin.

CROSS-REFERENCE

This application is a divisional of U.S. patent application Ser. No.13/532,289, filed Jun. 25, 2012, which is a continuation of U.S. patentapplication Ser. No. 13/345,560, filed Jan. 6, 2012 (now U.S. Pat. No.8,236,288); which claims the benefit of U.S. Provisional Application No.61/430,923, filed Jan. 7, 2011, all of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

Melanin in humans is the primary determinant of skin color. Melanin inskin is produced by melanocytes in the epidermis in response toenvironmental triggers, such as increased sun exposure, or otherphysical or chemical perturbation. Melanin is also found in hair, thepigmented tissue underlying the iris of the eye, as well as the striavascularis of the inner ear.

Environmental and/or physiological stress can cause disorders in melaninproduction. For example, post-inflammatory hyperpigmentation (“PIH”)represents the sequelae of various cutaneous disorders, includinginfections, allergic reactions, mechanical injuries, reactions tomedications, phototoxic eruptions, trauma (e.g., burns), inflammatorydiseases (e.g., lichen planus, lupus erythematosus and atopicdermatitis), as well as reactions to devices, including electromagneticdevices such as ultrasound, radiofrequency, lasers, light-emittingdiodes and visible light therapy, as well as microdermabrasionreactions. PIH occurs widely in the human population and can be thesource of significant psychosocial distress for those affected with thisdisorder. PIH is a pathophysiologic response to cutaneous inflammation.Melanocytes can be stimulated by the inflammatory process to synthesizeand secrete more melanin from melanocytes, or the number of melanocytescan increase in the epidermis, leading to hyperpigmentation of the skin.PIH can also occur when inflammation disrupts the basal cell layer,causing melanin pigment to be released and subsequently trapped bymacrophages in the papillary dermis. Hyperpigmentation or hypermelanosisdisorders due to environmental stressors, such as hormonal imbalance,can also affect melanin or pigmentation levels in the skin.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical and cosmetic compositions and methodsof treating disorders relating to pigmentation or melanin levels.Provided herein are pharmaceutical and cosmetic compositions and methodsof lightening skin. In some embodiments, the composition comprises asubstituted benzaldehyde such as, for example 4-ethoxybenzaldehye. Inother embodiments, the composition comprises a substituted benzaldehydeand at least one additional active agent. Certain embodiments disclosedherein provide a method for modulating PGF2-alpha levels. Otherembodiments provide a method for the treatment of pigmentation disorderscomprising administration of the composition to an individual. Theinventors of the present application identified for the first time thatthe compositions described herein may be use to treat post-inflammatoryhyperpigmentation (PIH), where inflammation is not treated. It was alsoindentified for the first time that the compositions described hereinlighten skin.

In one aspect, provided herein is a method is presented for modifyingmelanin distribution in an individual, the method comprisingadministering to the individual in need thereof an effective amount of acomposition comprising a substituted benzaldehyde and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In a particularembodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde. In yetanother embodiment, the substituted benzaldehyde is2-ethoxybenzaldehyde.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In certainembodiments, the composition is topically administered to the skin ofthe individual. In other embodiments, the composition is transdermallyadministered to the skin of the individual.

In some embodiments, the compositions further comprise at least oneadditional active agent. In some embodiments, the compositions furthercomprise at least two additional active agents. In some embodiments, thecompositions further comprise at least three additional active agents.An additional active agent may be, for example, an antioxidant, asunscreen, a sunprotectant, a sunblock, a skin-lightening agent, ananti-inflammatory agent, an anti-acne agent or mixtures thereof. Inother embodiments, the compositions further comprise one or more of asolvent, film former, preservative, viscosity increasing agent,fragrance, surfactant, chelating agent, humectant, or a combinationthereof. In yet another embodiment, a composition comprises anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In yet another embodiment, a composition comprisesniacinamide, butylene glycol, tetrahexyldecyl ascorbate, caprylic/caprictriglycerides, polyacrylate-13, cetyl ethylhexanoate, phenoxyethanol,hexylresorcinol, ethyl linoleate, polyisobutene, 4-ethoxybenzaldehyde,squalene, tocopherol, potassium sorbate, retinol, polysorbate 20,ethylhexylglycerine, phytic acid, disodium EDTA, dunaliella salinaextract and water.

In another embodiment, the compositions comprise a skin-lightening agentselected from the group of hydroquinone, monobenzyl ether ofhydroquinone, azelaic acid, kojic acid, mequinol, retinoids (e.g.,tretinoin, adapalene), soy proteins, alpha-hydroxy acids (e.g., glycolicacid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g., undecylenoyl phenylalanine),phytic acid or combinations thereof.

In one aspect, provided herein is a composition comprising from about0.01% to about 2% substituted benzaldehyde, about 0.01% to about 5.0%each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate, GlycyrrhizaGlabra (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In one embodiment,the amount of substituted benzaldehyde is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In another aspect, provided herein is a composition comprising fromabout 0.1% to about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0%each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate, GlycyrrhizaGlabra (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In one embodiment,the composition comprises from about 0.1% to about 0.75%, from about0.05% to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In yet another aspect, provided herein is a composition comprising about0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the compositioncomprises from about 0.1% to about 0.75%, from about 0.05% to about1.0%, or from about 0.01% to about 2% Retinol. In another embodiment,the composition comprises from about 2.0% to about 8.0%, from about 1%to about 10%, or from about 0.5% to about 15.0% Niacinamide. In anotherembodiment, the composition comprises from about 1.0% to about 5.0%,from about 0.5% to about 8.0%, or from about 0.1% to about 15%Tetrahexyldecyl Ascorbate. In another embodiment, the compositioncomprises from about 0.001% to about 0.5%, from about 0.0005% to about1.0% or from about 0.0001% to about 2% Licorice root extract. In anotherembodiment, the composition comprises from about 0.1% to about 3.0%,from about 0.05% to about 5.0%, or from about 0.01% to about 10.0%Resorcinol. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% ethyl linoleate.

Compositions described herein may be used to lighten skin as well as totreat hyperpigmentation or a hypermelanosis disorder. In one embodiment,the hyperpigmentation is post-inflammatory hyperpigmentation.Hyperpigmentation and hypermelanosis disorders may result from anenvironmental stressor, physiological stressor, or mechanical stressor.

Compositions described herein may reduce melanin distribution by about10% to about 40% when applied to skin.

Compositions described herein may further comprise one or moreadditional active agents. An additional active agent may be, forexample, an antioxidant, a sunscreen, a sunprotectant, a sunblock, askin-lightening agent, an anti-inflammatory agent, an anti-acne agent ormixtures thereof.

In one embodiment, an antioxidant is selected from the group of vitaminE, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin,resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium)extract, pomegranate extract, genistein, pycnogenol, curcumin,curcuminoids, Tocopherol, Dunaliella Salina Extract or combinationsthereof.

In one embodiment, a skin-lightening agent is selected from the group ofhydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojicacid, mequinol, retinoids, soy proteins, alpha-hydroxy acids,trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

Pharmaceutically or cosmetically acceptable carriers for use in thepresent compositions are topical carriers. The topical carrier may be awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

The compositions described herein may also further comprise one or moreof a solvent, film former, preservative, viscosity increasing agent,fragrance, surfactant, chelating agent, humectant, permeation enhancer,excipients, or a combination thereof.

In one embodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least one additional active agent, and apharmaceutically or cosmetically acceptable carrier. In otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least two additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least three additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least four additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least five additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least six additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least seven additional active agents, and apharmaceutically or cosmetically acceptable carrier.

In one embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least one additional active agent, and apharmaceutically or cosmetically acceptable carrier. In otherembodiment, a composition comprises about 0.5% 4-ethoxybenzaldehyde, atleast two additional active agents, and a pharmaceutically orcosmetically acceptable carrier. In yet other embodiment, a compositioncomprises about 0.5% 4-ethoxybenzaldehyde, at least three additionalactive agents, and a pharmaceutically or cosmetically acceptablecarrier. In yet other embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least four additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises about 0.5% 4-ethoxybenzaldehyde, atleast five additional active agents, and a pharmaceutically orcosmetically acceptable carrier. In yet other embodiment, a compositioncomprises about 0.5% 4-ethoxybenzaldehyde, at least six additionalactive agents, and a pharmaceutically or cosmetically acceptablecarrier. In yet other embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least seven additional active agents, and apharmaceutically or cosmetically acceptable carrier.

In one embodiment, a composition comprises from about 0.1% to about 0.5%4-ethoxybenzaldehyde, at least one skin lightening agent, at least oneskin conditioning agent, at least one antioxidant, at least oneocclusive, at least one emollient, at least one preservative, at leastone viscosity increasing agent, at least one fragrance, at least oneskin conditioning agent, at least one surfactant, at least one chlatingagent, at least one humectant, and a pharmaceutically or cosmeticallyacceptable carrier.

On another embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least one skin lightening agent, at least oneskin conditioning agent, at least one antioxidant, at least oneocclusive, at least one emollient, at least one preservative, at leastone viscosity increasing agent, at least one fragrance, at least oneskin conditioning agent, at least one surfactant, at least one chlatingagent, at least one humectant, and a pharmaceutically or cosmeticallyacceptable carrier.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 10%, by about 15%, by about 20%, by about25%, by about 30%, by about 35%, by about 40%, by about 45%, by about50%, by about 55%, by about 60%, by about 65%, by about 70%, by about75%, by about 80%, by about 85%, by about 90%, by about 95% or by about100%. In another embodiment, the substituted benzaldehyde compositionreduces melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 5% to about 50%. Inyet another embodiment, the substituted benzaldehyde composition reducesmelanin distribution by about 10% to about 40%.

Another aspect relates to a method of modifying melanin distribution inan individual, the method comprising contacting keratinocytes with aneffective amount of a composition comprising a substituted benzaldehydeand a pharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a particular embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In certainembodiments, the composition is topically administered to the skin ofthe individual. In other embodiments, the composition is transdermallyadministered to the skin of the individual.

In some embodiments, the compositions further comprise at least oneadditional active agent. In particular embodiments, an additional activeagent may be, for example, an antioxidant, a sunscreen, a sunprotectant,a sunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. In yet another embodiment, thecompositions comprise an antioxidant selected from the group ofniacinamide, vitamin E, Coenzyme Q10, idebenone, lycopene, green teapolyphenols, silybin, resveratrol, grape seed extract, Oregon grape root(Mahonia aquifolium) extract, pomegranate extract, genistein,pycnogenol, curcumin, curcuminoids, or combinations thereof. In anotherembodiment, the compositions comprise a skin-lightening agent selectedfrom the group of hydroquinone, monobenzyl ether of hydroquinone,azelaic acid, kojic acid, mequinol, retinoids (e.g., tretinoin,adapalene), soy proteins, alpha-hydroxy acids (e.g., glycolic acid),trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 10%, by about 15%, by about 20%, by about25%, by about 30%, by about 35%, by about 40%, by about 45%, by about50%, by about 55%, by about 60%, by about 65%, by about 70%, by about75%, by about 80%, by about 85%, by about 90%, by about 95% or by about100%. In other embodiments, the substituted benzaldehyde compositionreduces melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 5% to about 50%. Inyet another embodiment, the substituted benzaldehyde composition reducesmelanin distribution by about 10% to about 40%.

In a further aspect, provided herein is a method of treating a melanindisorder in an individual comprising contacting keratinocytes with aneffective amount of a composition comprising a substituted benzaldehydeand a pharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In oneembodiment, the cell is present in an individual. In another embodiment,the composition is topically administered to the skin of the individual.In yet another embodiment, the composition is transdermally administeredto the skin of the individual.

In some embodiments, the compositions further comprise an additionalactive agent. In particular embodiments, the additional active agent isan antioxidant, a sunscreen, a sunprotectant, a sunblock, askin-lightening agent, an anti-inflammatory agent, an anti-acne agent ormixtures thereof. In yet another embodiment, the compositions comprisean antioxidant selected from the group of niacinamide, vitamin E,Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin,resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium)extract, pomegranate extract, genistein, pycnogenol, curcumin,curcuminoids, or combinations thereof. In another embodiment, thecompositions comprise a skin-lightening agent selected from the group ofhydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojicacid, mequinol, retinoids (e.g., tretinoin, adapalene), soy proteins,alpha-hydroxy acids (e.g., glycolic acid), trichloroacetic acid,salicylic acid, hydroquinone-beta-D-glucopyranoside, paper mulberry,glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In a particular embodiment, the substituted benzaldehyde compositionmodifies melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 10%, by about 15%, byabout 20%, by about 25%, by about 30%, by about 35%, by about 40%, byabout 45%, by about 50%, by about 55%, by about 60%, by about 65%, byabout 70%, by about 75%, by about 80%, by about 85%, by about 90%, byabout 95% or by about 100%. In another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 5% toabout 50%. In yet another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 10% to about 40%.

In some embodiments, provided herein is a method of treating ahyperpigmentation skin disorder in an individual in need thereof, themethod comprising administering to the skin of the individual aneffective amount of a composition comprising a substituted benzaldehydeand a pharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the hyperpigmentation skin disorder results from anenvironmental stressor, physiological stressor, or mechanical stressor.In a particular embodiment, the physiological stressor is a hormonaldisorder. In yet another embodiment, the environmental stressor isexcessive sun exposure or chemical exposure.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In some embodiments, the compositions further comprise an additionalactive agent. In particular embodiments, the additional active agent isan antioxidant, a sunscreen, a sunprotectant, a sunblock, askin-lightening agent, an anti-inflammatory agent, an anti-acne agent ormixtures thereof. In yet another embodiment, the compositions comprisean antioxidant selected from the group of niacinamide, vitamin E,Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin,resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium)extract, pomegranate extract, genistein, pycnogenol, curcumin,curcuminoids, or combinations thereof. In another embodiment, thecompositions comprise a skin-lightening agent selected from the group ofhydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojicacid, mequinol, retinoids (e.g., tretinoin, adapalene), soy proteins,alpha-hydroxy acids (e.g., glycolic acid), trichloroacetic acid,salicylic acid, hydroquinone-beta-D-glucopyranoside, paper mulberry,glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In a particular embodiment, the substituted benzaldehyde compositionmodifies melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 10%, by about 15%, byabout 20%, by about 25%, by about 30%, by about 35%, by about 40%, byabout 45%, by about 50%, by about 55%, by about 60%, by about 65%, byabout 70%, by about 75%, by about 80%, by about 85%, by about 90%, byabout 95% or by about 100%. In another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 5% toabout 50%. In yet another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 10% to about 40%.

In some embodiments, provided herein are methods of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: from about 0.01% to about 2%substituted benzaldehyde and a pharmaceutically or cosmeticallyacceptable carrier.

In one embodiment, the method further comprises administering to theindividual in need thereof an effective amount of about 0.01% to about5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol, ethyllinoleate. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

In another aspect, provided herein is a method of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: from about 0.01% to about 2%substituted benzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the amount ofsubstituted benzaldehyde is between about 0.1% to about 0.5%. In anotherembodiment, the amount of substituted benzaldehyde in the composition isabout 0.5%. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In another aspect, provided herein is a method of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: from about 0.1% to about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In another aspect, provided herein is a method of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: about 0.5% 4-ethoxybenzaldehyde,about 0.01% to about 5.0% each of Retinol, Niacinamide, TetrahexyldecylAscorbate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol,ethyl linoleate, and a pharmaceutically or cosmetically acceptablecarrier. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

In some embodiments, the method reduces melanin distribution by about10% to about 40%.

Application of the compositions in the methods described herein may betopical or transdermal administration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

In one embodiment, hyperpigmentation may result from an environmentalstressor (e.g., excessive sun exposure or chemical exposure),physiological stressor (e.g., a hormonal disorder), or mechanicalstressor.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipients, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, or combinationsthereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

In another aspect, provided herein is a method of lightening skin in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising: from about 0.01% toabout 2% substituted benzaldehyde, about 0.01% to about 5.0% each ofRetinol, Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra(Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In one embodiment,the amount of substituted benzaldehyde in the composition is about 0.5%.In another embodiment, the composition comprises from about 0.1% toabout 0.75%, from about 0.05% to about 1.0%, or from about 0.01% toabout 2% Retinol. In another embodiment, the composition comprises fromabout 2.0% to about 8.0%, from about 1% to about 10%, or from about 0.5%to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.1% to about 0.5%.

In another aspect, provided herein is a method of lightening skin in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising: about 0.1% to about0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the amount ofsubstituted benzaldehyde in the composition is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In yet another aspect, provided herein is a method of lightening skin inan individual, comprising administering to the individual in needthereof an effective amount of a composition comprising: about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the amount ofsubstituted benzaldehyde in the composition is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Also provided is a method of lightening skin in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: from about 0.01% to about 2%substituted benzaldehyde and a pharmaceutically or cosmeticallyacceptable carrier.

In one embodiment, the method further comprises administering to theindividual in need thereof an effective amount of about 0.01% to about5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol, ethyllinoleate. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

In some embodiments, the methods decrease the level of pigmentation byabout 5%, by about 10%, by about 20%, by about 30% or by about 40%.

The methods may be used to treat hyperpigmentation or a hypermelanosisdisorder. In one embodiment, hyperpigmentation may result from anenvironmental stressor (e.g., excessive sun exposure or chemicalexposure), physiological stressor (e.g., a hormonal disorder), ormechanical stressor.

In some embodiments, the method reduces melanin distribution by about10% to about 40%.

Application of the compositions in the methods described herein may betopical or transdermal administration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipient, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol,Dunaliella Salina Extract or combinations thereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

Provided herein are methods of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in a cell, comprisingcontacting said cell with a composition comprising from about 0.01% toabout 2% substituted benzaldehyde and a pharmaceutically or cosmeticallyacceptable carrier.

In one embodiment, the method further comprises administering to theindividual in need thereof an effective amount of about 0.01% to about5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol, ethyllinoleate.

Provided is a method of modifying melanin distribution by modulatingprostaglandin F2 alpha (PGF2 alpha) in skin cells in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising from about 0.01% to about 2%substituted benzaldehyde and a pharmaceutically or cosmeticallyacceptable carrier.

In one embodiment, the method further comprises administering to theindividual in need thereof an effective amount of about 0.01% to about5.0% each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol, ethyllinoleate. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Provided is a method of modifying melanin distribution by modulatingprostaglandin F2 alpha (PGF2 alpha) in a cell, comprising contactingsaid cell with a composition comprising from about 0.01% to about 2%substituted benzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the cells beingtreated are located in skin of an individual. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Provided is a method of modifying melanin distribution by modulatingprostaglandin F2 alpha (PGF2 alpha) in skin cells in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising from about 0.01% to about 2%substituted benzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In one embodiment, the amount of substituted benzaldehyde is betweenabout 0.1% to about 0.5%. In one embodiment, the amount of substitutedbenzaldehyde in the composition is about 0.5%.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.1% to about 0.5%. In oneembodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde, whichmay be present in the composition in an amount of about 0.5%.

Also provided are methods of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in a cell, comprisingcontacting said cell with a composition comprising about 0.1% to about0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the cells beingtreated are located in skin of an individual. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Provided herein is a method of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in a cell, comprisingcontacting said cell with a composition comprising about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the cells beingtreated are located in skin of an individual. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Also disclosed are methods of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in skin cells in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the methodreduces melanin distribution by about 10% to about 40%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Application of the compositions in the methods described herein may betopical or transdermal administration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipient, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol,Dunaliella Salina Extract or combinations thereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

In some embodiments, provided herein is a method of modifying melanindistribution in an individual, the method comprising administering tothe individual in need thereof an effective amount of a compositioncomprising a substituted benzaldehyde, at least one additional activeagent and a pharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 10%, by about 15%, by about 20%, by about25%, by about 30%, by about 35%, by about 40%, by about 45%, by about50%, by about 55%, by about 60%, by about 65%, by about 70%, by about75%, by about 80%, by about 85%, by about 90%, by about 95% or by about100%. In other embodiments, the substituted benzaldehyde compositionreduces melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 5% to about 50%. Inyet another embodiment, the substituted benzaldehyde composition reducesmelanin distribution by about 10% to about 40%.

In a further aspect, provided herein is a method of modifying melanindistribution in an individual, the method comprising contactingkeratinocytes with an effective amount of a composition comprising asubstituted benzaldehyde, at least one additional active agent and apharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 10%, by about 15%, by about 20%, by about25%, by about 30%, by about 35%, by about 40%, by about 45%, by about50%, by about 55%, by about 60%, by about 65%, by about 70%, by about75%, by about 80%, by about 85%, by about 90%, by about 95% or by about100%. In other embodiments, the substituted benzaldehyde compositionreduces melanin distribution by about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In another embodiment, the substituted benzaldehydecomposition reduces melanin distribution by about 5% to about 50%. Inyet another embodiment, the substituted benzaldehyde composition reducesmelanin distribution by about 10% to about 40%.

In another aspect, provided herein is a method of treating a melanindisorder in an individual, the method comprising contactingkeratinocytes with an effective amount of a composition comprising asubstituted benzaldehyde, at least one additional active agent and apharmaceutically or cosmetically acceptable carrier. In someembodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the compositions further comprise apharmaceutically or cosmetically acceptable carrier. In anotherembodiment, the pharmaceutically or cosmetically acceptable carrier isan oral or topical carrier. In other embodiments, the pharmaceuticallyor cosmetically acceptable topical carrier is a water-in-oil emulsion,cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion,oil-in-water emulsion, water-in-oil-in-water emulsion, water-in-siliconeemulsion, spray or serum carrier. In some embodiments, the cell ispresent on skin of an individual. In another embodiment, the compositionis topically administered to the skin of the individual. In yet anotherembodiment, the composition is transdermally administered to the skin ofthe individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In some embodiments, the composition modifies melanin distribution byabout 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, by about 15%, by about 20%, by about 25%,by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, byabout 55%, by about 60%, by about 65%, by about 70%, by about 75%, byabout 80%, by about 85%, by about 90%, by about 95% or by about 100%. Inother embodiments, the composition reduces melanin distribution by about10%, by about 15%, by about 20%, by about 25%, by about 30%, by about35%, by about 40%, by about 45%, by about 50%, by about 55%, by about60%, by about 65%, by about 70%, by about 75%, by about 80%, by about85%, by about 90%, by about 95% or by about 100%. In another embodiment,the substituted benzaldehyde composition reduces melanin distribution byabout 5% to about 50%. In yet another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10% toabout 40%.

In some embodiments, provided herein is a method of treating ahyperpigmentation skin disorder in an individual in need thereof, themethod comprising administering to the skin of the individual aneffective amount of a composition comprising a substituted benzaldehyde,at least one additional active agent and a pharmaceutically orcosmetically acceptable carrier. In some embodiments, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In a specificembodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde. In yetanother embodiment, the substituted benzaldehyde is2-ethoxybenzaldehyde.

In some embodiments, the individual suffers from a hyperpigmentationdisorder resulting from an environmental stressor, physiologicalstressor or mechanical stressor. In a particular embodiment, thephysiological stressor is a hormonal disorder. In yet anotherembodiment, the environmental stressor is excessive sun exposure orchemical exposure.

In another embodiment, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine),phytic acid or combinations thereof.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 1%, about 2%, about 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, about 10%, by about 15%, byabout 20%, by about 25%, by about 30%, by about 35%, by about 40%, byabout 45%, by about 50%, by about 55%, by about 60%, by about 65%, byabout 70%, by about 75%, by about 80%, by about 85%, by about 90%, byabout 95% or by about 100%. In other embodiments, the substitutedbenzaldehyde composition reduces melanin distribution by about 10%, byabout 15%, by about 20%, by about 25%, by about 30%, by about 35%, byabout 40%, by about 45%, by about 50%, by about 55%, by about 60%, byabout 65%, by about 70%, by about 75%, by about 80%, by about 85%, byabout 90%, by about 95% or by about 100%. In another embodiment, thesubstituted benzaldehyde composition reduces melanin distribution byabout 5% to about 50%. In yet another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10% toabout 40%.

In a further aspect, provided herein is a method of modulating the skinpigmentation of an individual, the method comprising administering tothe skin of the individual an effective amount of a compositioncomprising a substituted benzaldehyde, at least one additional activeagent and a pharmaceutically or cosmetically acceptable carrier, whereinthe substituted benzaldehyde modulates PGF2-alpha in said individual. Insome embodiments, the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde.In a specific embodiment, the substituted benzaldehyde is4-ethoxybenzaldehyde. In yet another embodiment, the substitutedbenzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the individual suffers from a hyperpigmentationdisorder resulting from an environmental stressor, physiologicalstressor or mechanical stressor. In a particular embodiment, thephysiological stressor is a hormonal disorder. In yet anotherembodiment, the environmental stressor is excessive sun exposure orchemical exposure.

In another embodiment, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic acid combinations thereof.

In some embodiments, the composition modifies melanin distribution byabout 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, by about 15%, by about 20%, by about 25%,by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, byabout 55%, by about 60%, by about 65%, by about 70%, by about 75%, byabout 80%, by about 85%, by about 90%, by about 95% or by about 100%. Inother embodiments, the composition reduces melanin distribution by about10%, by about 15%, by about 20%, by about 25%, by about 30%, by about35%, by about 40%, by about 45%, by about 50%, by about 55%, by about60%, by about 65%, by about 70%, by about 75%, by about 80%, by about85%, by about 90%, by about 95% or by about 100%. In another embodiment,the substituted benzaldehyde composition reduces melanin distribution byabout 5% to about 50%. In yet another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10% toabout 40%.

Another aspect provided herein relates to a method of modifying melanindistribution by modulating prostaglandin F2 alpha (PGF2 alpha) in acell, the method comprising contacting said cell with a compositioncomprising a substituted benzaldehyde. In a particular embodiment, thecomposition modulates PGF2 alpha in a keratinocyte cell to modifymelanin distribution. In some embodiments, the substituted benzaldehydeis 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or4-propoxybenzaldehyde. In a specific embodiment, the substitutedbenzaldehyde is 4-ethoxybenzaldehyde. In yet another embodiment, thesubstituted benzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the compositions further comprise apharmaceutically or cosmetically acceptable carrier. In anotherembodiment, the pharmaceutically or cosmetically acceptable carrier isan oral or topical carrier. In other embodiments, the pharmaceuticallyor cosmetically acceptable topical carrier is a water-in-oil emulsion,cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion,oil-in-water emulsion, water-in-oil-in-water emulsion, water-in-siliconeemulsion, spray or serum carrier. In certain embodiments, thecomposition is topically administered to the skin of the individual. Inother embodiments, the composition is transdermally administered to theskin of the individual.

In some embodiments, the compositions further comprise an additionalactive agent. In particular embodiments, the additional active agent isan antioxidant, a sunscreen, a sunprotectant, a sunblock, askin-lightening agent, an anti-inflammatory agent, an anti-acne agent ormixtures thereof. In yet another embodiment, the compositions comprisean antioxidant selected from the group of niacinamide, vitamin E,Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin,resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium)extract, pomegranate extract, genistein, pycnogenol, curcumin,curcuminoids, or combinations thereof. In another embodiment, thecompositions comprise a skin-lightening agent selected from the group ofhydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojicacid, mequinol, retinoids (e.g., tretinoin, adapalene), soy proteins,alpha-hydroxy acids (e.g., glycolic acid), trichloroacetic acid,salicylic acid, hydroquinone-beta-D-glucopyranoside, paper mulberry,glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic acid combinations thereof.

In some embodiments, the substituted benzaldehyde composition modifiesmelanin distribution by about 1%, about 2%, about 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, about 10%, by about 15%, byabout 20%, by about 25%, by about 30%, by about 35%, by about 40%, byabout 45%, by about 50%, by about 55%, by about 60%, by about 65%, byabout 70%, by about 75%, by about 80%, by about 85%, by about 90%, byabout 95% or by about 100%. In another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10%, byabout 15%, by about 20%, by about 25%, by about 30%, by about 35%, byabout 40%, by about 45%, by about 50%, by about 55%, by about 60%, byabout 65%, by about 70%, by about 75%, by about 80%, by about 85%, byabout 90%, by about 95% or by about 100%. In another embodiment, thesubstituted benzaldehyde composition reduces melanin distribution byabout 5% to about 50%. In yet another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10% toabout 40%.

In a further aspect, provided herein is a method of modifying melanindistribution by modulating prostaglandin F2 alpha (PGF2 alpha) in acell, the method comprising contacting said cell with a compositioncomprising a substituted benzaldehyde and at least one additional activeagent. In some embodiments, the substituted benzaldehyde is2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or4-propoxybenzaldehyde. In a specific embodiment, the substitutedbenzaldehyde is 4-ethoxybenzaldehyde. In yet another embodiment, thesubstituted benzaldehyde is 2-ethoxybenzaldehyde.

In some embodiments, the compositions further comprise apharmaceutically or cosmetically acceptable carrier. In anotherembodiment, the pharmaceutically or cosmetically acceptable carrier isan oral or topical carrier. In other embodiments, the pharmaceuticallyor cosmetically acceptable topical carrier is a water-in-oil emulsion,cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion,oil-in-water emulsion, water-in-oil-in-water emulsion, water-in-siliconeemulsion, spray or serum carrier. In another embodiment, the compositionis topically administered to the skin of the individual. In yet anotherembodiment, the composition is transdermally administered to the skin ofthe individual.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic acid combinations thereof.

In some embodiments, the composition modifies melanin distribution byabout 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, by about 15%, by about 20%, by about 25%,by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, byabout 55%, by about 60%, by about 65%, by about 70%, by about 75%, byabout 80%, by about 85%, by about 90%, by about 95% or by about 100%. Inother embodiments, the composition reduces melanin distribution by about10%, by about 15%, by about 20%, by about 25%, by about 30%, by about35%, by about 40%, by about 45%, by about 50%, by about 55%, by about60%, by about 65%, by about 70%, by about 75%, by about 80%, by about85%, by about 90%, by about 95% or by about 100%. In another embodiment,the substituted benzaldehyde composition reduces melanin distribution byabout 5% to about 50%. In yet another embodiment, the substitutedbenzaldehyde composition reduces melanin distribution by about 10% toabout 40%.

In a particular embodiment, the compositions disclosed herein modulatePGF2 alpha in a keratinocyte cell to modify melanin distribution. Insome embodiments, the compositions disclosed herein modulate PGF2.

In a further aspect, provided herein are compositions comprising acombination of a substituted benzaldehyde, at least one additionalactive agent, and a pharmaceutically or cosmetically acceptable carrier.In some embodiments, the substituted benzaldehyde is2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or4-propoxybenzaldehyde. In a specific embodiment, the substitutedbenzaldehyde is 4-ethoxybenzaldehyde. In yet another embodiment, thesubstituted benzaldehyde is 2-ethoxybenzaldehyde. In some embodiments,the substituted benzaldehyde is a skin lightening agent.

In another embodiment, the pharmaceutically or cosmetically acceptablecarrier is an oral or topical carrier. In other embodiments, thepharmaceutically or cosmetically acceptable topical carrier is awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier. In anotherembodiment, the composition is topically administered to the skin of theindividual. In yet another embodiment, the composition is transdermallyadministered to the skin of the individual.

In another embodiment, an amount of the substituted benzaldehyde that iseffective in reducing melanin levels in a subject is present in thecomposition. In some embodiments, the composition modifies melanindistribution by about 1%, about 2%, about 3%, about 4%, about 5%, about6%, about 7%, about 8%, about 9%, about 10%, by about 15%, by about 20%,by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 65%, by about 70%, byabout 75%, by about 80%, by about 85%, by about 90%, by about 95% or byabout 100%. In other embodiments, the composition reduces melanindistribution by about 10%, by about 15%, by about 20%, by about 25%, byabout 30%, by about 35%, by about 40%, by about 45%, by about 50%, byabout 55%, by about 60%, by about 65%, by about 70%, by about 75%, byabout 80%, by about 85%, by about 90%, by about 95% or by about 100%. Inanother embodiment, the substituted benzaldehyde composition reducesmelanin distribution by about 5% to about 50%. In yet anotherembodiment, the substituted benzaldehyde composition reduces melanindistribution by about 10% to about 40%.

In particular embodiments, the additional active agent is anantioxidant, a sunscreen, a sunprotectant, a sunblock, a skin-lighteningagent, an anti-inflammatory agent, an anti-acne agent or mixturesthereof. In yet another embodiment, the compositions comprise anantioxidant selected from the group of niacinamide, vitamin E, CoenzymeQ10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol,grape seed extract, Oregon grape root (Mahonia aquifolium) extract,pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, orcombinations thereof. In another embodiment, the compositions comprise askin-lightening agent selected from the group of hydroquinone,monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol,retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxyacids (e.g., glycolic acid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, licorice extract (e.g., Glycyrrhiza Glabra (licorice) rootextract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic acid combinations thereof.

Another aspect provided herein relates to the use of the composition totreat a hyperpigmentation disorder. In some embodiments, thehyperpigmentation disorder is due to post-inflammatory hyperpigmentationdisorder. In other embodiments, the post-inflammatory hyperpigmentationdisorder is due to infections, allergic reactions, mechanical injuries,reaction to medications, phototoxic eruptions, trauma, or reaction toultrasound, radiofrequency, lasers, light-emitting diodes, visible lighttherapy, microdermabrasion or chemical peel therapies.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the embodiments are set forth with particularityin the appended claims. A better understanding of the features andadvantages of the present embodiments will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the invention are utilized, andthe accompanying drawings of which:

FIG. 1 is a graph that depicts 4-ethoxybenzaldehyde (“4EB”)dose-dependent inhibition of PGF2 alpha in UVB-induced keratinocytes.Keratinocytes treated with indomethacin are used as a positive control.

FIG. 2 is a graph depicting the protection factors assessed from thepost-inflammatory hyperpigmentation clinical study.

FIG. 3 is a graph depicting the reduction in hyperpigmentation assessedfrom the post-inflammatory hyperpigmentation clinical study.

FIG. 4 is a graph depicting the increase in skin brightness (L*)assessed from the post-inflammatory hyperpigmentation clinical study.

FIG. 5 is a graph depicting the reduction of melanin content in humanskin equivalent treated with a negative control, positive control (1%Kojic acid) or Base+1% 4EB.

FIG. 6 is a graph depicting the increase in brightness of UV-inducedpigmentation where human skin is left untreated, or is treated with 4%hydroquinone or Base+0.5% 4EB.

FIG. 7 is a graph depicting the decrease in hyperpigmentation comparedto baseline after treatment with 4% hydroquinone or Base+0.5% 4EB.

FIG. 8 is a graph depicting the distribution of results in individualsubjects after treatment with 4% hydroquinone or Base+0.5% 4EB.

FIG. 9 is a graph depicting the results from the patient self-assessmentquestionnaire after treatment with 4% hydroquinone or Base+0.5% 4EB.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to compositions comprising substitutedbenzaldehydes and optionally at least one additional active agent, andmethods for using the compositions. The compositions disclosed may beused for the treatment of skin disorders, including the treatment ofmelanin or pigmentation disorders, including but not limited tohyperpigmentation or hypermelanosis disorders that affect melanin orpigmentation levels in the skin. Such disorders may be due toenvironmental stressors, such as excessive sun, or physiologicalstressors, such as hormonal imbalance. Such disorders include melasma,chloasma, post-inflammatory hyperpigmentation, acanthosis nigricans,pigmented purpura, urticaria, pityriasis, solar lentigines, vitiligo,birthmarks, port-wine stains, dark spots, age spots, freckles or sunspots. Other examples of uses of the disclosed compositions includehyper or hypopigmentation due to scarring, or exposure to environmentalantigens or allergens, including phytodermatitis orphytophotodermatitis. In addition, the disclosed compositions may beused in conjunction with and/or for the treatment of skin disorders ortrauma as a result of a mechanical injury or therapy, including but notlimited to laser treatment, chemical peels, intense pulsed light,dermabrasion or cryotherapy.

The disclosed compositions may modify melanin and/or melanocytedistribution and/or levels for the treatment of melanin or pigmentationdisorders. The disclosed compositions may modify melanin and/ormelanocyte distribution and/or levels by about 1%, about 2%, about 3%,about 4%, about 5%, about 6%, by about 7%, about 7%, about 8%, about 9%,by about 10%, by about 12%, by about 15%, by about 20%, by about 25%, byabout 30%, by about 35%, by about 35%, by about 40%, by about 45%, byabout 50%, by about 55%, by about 60%, by about 70%, by about 80%, byabout 90%, by about 100%, by about 125% or by about 150%. The disclosedcompositions may decrease or increase melanin and/or melanocytedistribution and/or levels. For example, in the treatment ofhyperpigmentation or hypermelanosis disorders, the disclosedcompositions may decrease melanin and/or melanocyte distribution and/orlevels by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, byabout 7%, about 7%, about 8%, about 9%, by about 10%, by about 12%, byabout 15%, by about 20%, by about 25%, by about 30%, by about 35%, byabout 35%, by about 40%, by about 45%, by about 50%, by about 55%, byabout 60%, by about 70%, by about 80%, by about 90% or by about 100%. Inanother embodiment, melanin distribution may be decreased by about 5% toabout 50%. In yet another embodiment, melanin distribution may bedecreased by about 10% to about 40%. The disclosed compositions mayoptionally modify or treat other cosmetic or therapeutic disorders,including dry skin, eczema or other cosmetic or dermatologicaldisorders. The formulations disclosed herein may comprise a form fortopical administration, including a lotion, emulsion, cream, gel,ointment, foam, liquid, paste or other topically administrable form.Alternatively, the formulations disclosed herein may comprise a formsuitable for transdermal administration, including a transdermal patch,transdermal lotion, transdermal cream, transdermal gel, transdermalointment, transdermal foam, transdermal liquid, transdermal paste orother transdermally-administrable form.

In some embodiments, an additional active agent(s) may be used incombination with the substituted benzaldehyde compositions disclosed.For example, other skin lightening agents may be used in combinationwith the substituted benzaldehydes, including hydroquinone, retinoids,corticosteroids, glycolic acid, other fruit acids, azelaic acid, vitaminC, licorice extract (e.g., Glycyrrhiza Glabra (licorice) root extract),an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phytic acidor mixtures thereof. In addition, skin or dermatological agents may alsobe used in combination with the substituted benzaldehyde compositionsdisclosed herein, including antioxidants, sunscreen and sunprotectants,emollients, barrier treatments, topical steroids, antibiotics,antimicrobials, acne medications, antiperspirants, deodorants, perfumingagents and other skin or dermatological agents or mixtures thereof.Alternatively, pre, simultaneous or subsequent dermatological treatmentsmay also take place in combination with the compositions disclosedherein, including laser treatment, chemical peels, intense pulsed light,dermabrasion or cryotherapy.

In one aspect, provided herein is a composition comprising from about0.01% to about 2% substituted benzaldehyde, about 0.01% to about 5.0%each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate, GlycyrrhizaGlabra (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In one embodiment,the amount of substituted benzaldehyde is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In another aspect, provided herein is a comprising from 0.1% to about0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In yet another aspect, provided herein is a comprising about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Compositions described herein may be used to lighten skin as well as totreat hyperpigmentation or a hypermelanosis disorder. In one embodiment,the hyperpigmentation is post-inflammatory hyperpigmentation.Hyperpigmentation and hypermelanosis disorders may result from anenvironmental stressor, physiological stressor, or mechanical stressor.

Compositions described herein may reduce melanin distribution by about10% to about 40% when applied to skin.

Compositions described herein may further comprise one or moreadditional active agents. An additional active agent may be, forexample, an antioxidant, a sunscreen, a sunprotectant, a sunblock, askin-lightening agent, an anti-inflammatory agent, an anti-acne agent ormixtures thereof.

In one embodiment, an antioxidant is selected from the group of vitaminE, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin,resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium)extract, pomegranate extract, genistein, pycnogenol, curcumin,curcuminoids, Tocopherol, Dunaliella Salina Extract or combinationsthereof.

In one embodiment, a skin-lightening agent is selected from the group ofhydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojicacid, mequinol, retinoids, soy proteins, alpha-hydroxy acids,trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

Pharmaceutically or cosmetically acceptable carriers for use in thepresent compositions are topical carriers. The topical carrier may be awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

The compositions described herein may also further comprise one or moreof a solvent, film former, preservative, viscosity increasing agent,fragrance, surfactant, chelating agent, humectant, permeation enhancer(skin penetrator), excipients, or a combination thereof.

In one embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least one additional active agent, and apharmaceutically or cosmetically acceptable carrier. In otherembodiment, a composition comprises about 0.5% 4-ethoxybenzaldehyde, atleast two additional active agents, and a pharmaceutically orcosmetically acceptable carrier. In yet other embodiment, a compositioncomprises about 0.5% 4-ethoxybenzaldehyde, at least three additionalactive agents, and a pharmaceutically or cosmetically acceptablecarrier. In yet other embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least four additional active agents, and apharmaceutically or cosmetically acceptable carrier. In yet otherembodiment, a composition comprises about 0.5% 4-ethoxybenzaldehyde, atleast five additional active agents, and a pharmaceutically orcosmetically acceptable carrier. In yet other embodiment, a compositioncomprises about 0.5% 4-ethoxybenzaldehyde, at least six additionalactive agents, and a pharmaceutically or cosmetically acceptablecarrier.

In another embodiment, a composition comprises from about 0.1% to about0.5% 4-ethoxybenzaldehyde, at least one skin lightening agent, at leastone skin conditioning agent, at least one antioxidant, at least oneocclusive, at least one emollient, at least one preservative, at leastone viscosity increasing agent, at least one fragrance, at least oneskin conditioning agent, at least one surfactant, at least one chelatingagent, at least one humectant, and a pharmaceutically or cosmeticallyacceptable carrier.

In another embodiment, a composition comprises about 0.5%4-ethoxybenzaldehyde, at least one skin lightening agent, at least oneskin conditioning agent, at least one antioxidant, at least oneocclusive, at least one emollient, at least one preservative, at leastone viscosity increasing agent, at least one fragrance, at least oneskin conditioning agent, at least one surfactant, at least one chelatingagent, at least one humectant, and a pharmaceutically or cosmeticallyacceptable carrier. In another embodiment, the composition comprisesfrom about 0.1% to about 0.75%, from about 0.05% to about 1.0%, or fromabout 0.01% to about 2% Retinol. In another embodiment, the compositioncomprises from about 2.0% to about 8.0%, from about 1% to about 10%, orfrom about 0.5% to about 15.0% Niacinamide. In another embodiment, thecomposition comprises from about 1.0% to about 5.0%, from about 0.5% toabout 8.0%, or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate.In another embodiment, the composition comprises from about 0.001% toabout 0.5%, from about 0.0005% to about 1.0% or from about 0.0001% toabout 2% Licorice root extract. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% Resorcinol. In another embodiment,the composition comprises from about 0.1% to about 3.0%, from about0.05% to about 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

In some embodiments, the combination compositions disclosed herein mayact additively or synergistically. In some embodiments, a “synergisticeffect” may be seen where the combination of the substitutedbenzaldehyde and additional active agent(s) results in an activity thatis more than the effect of the two individual agents alone. In otherembodiments, a “synergistic effect” may be seen where a combination ofthe substituted benzaldehyde and additional active agent(s) results in amodulation in melanin distribution, but no effect is seen when theagents are used individually. In yet other embodiments, a “synergisticeffect” may allow a decrease in the amount of substituted benzaldehydeand/or additional active agent(s) used, thereby decreasing the incidenceof adverse side effects, such as itching, pruritis, skin irritation orother adverse side effects.

As used in the specification and the appended claims, the singular forms“a”, “an” and “the” include plural references unless the context clearlydictates otherwise. Thus for example, reference to “the method” includesone or more methods, and/or steps of the type described herein and/orwhich will become apparent to those persons skilled in the art uponreading this disclosure.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, preferably up to 10%, more preferably up to 5%, and morepreferably still up to 1% of a given value. Alternatively, particularlywith respect to biological systems or processes, the term can meanwithin an order of magnitude, preferably within 5-fold, and morepreferably within 2-fold, of a value. Where particular values aredescribed in the application and claims, unless otherwise stated theterm “about” meaning within an acceptable error range for the particularvalue should be assumed.

As used herein, the term “acyl” refers to a radical formed by removal ofa hydroxyl group from an organic acid and has the general formula—C(O)—X where X is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acyloxy” refers to the group or radical —OC(O)R23 where R23 ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl or substituted or unsubstituted cycloalkyl.

The term “alkyl” as used herein refers to saturated or unsaturated,straight- or branched-chain hydrocarbon radicals derived from ahydrocarbon moiety containing between one and twenty carbon atoms byremoval of a single hydrogen atom. Alkyl groups as used herein mayoptionally include one or more further substituent groups. This term isexemplified by groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and thelike, and may be substituted or unsubstituted. The term “lower alkyl”refers to alkyl groups having 1 to 6 carbon atoms. The term “alkyl” alsoincludes “cycloalkyls” as defined below.

“Alkynyl” refers to acetylenically or alkynically unsaturatedhydrocarbyl groups particularly having 2 to 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude substituted or unsubstituted acetylenic, substituted orunsubstituted ethynyl (—C≡CH), substituted or unsubstituted propargyl(—CH2C≡CH), and the like.

The term “aminoalkyl” as used herein, refers to an amino substitutedalkyl radical. This term is meant to include alkyl groups having anamino substituent at any position and wherein the alkyl group attachesthe aminoalkyl group to the parent molecule. The alkyl and/or aminoportions of the aminoalkyl group can be further substituted withsubstituent groups.

As used herein, the term “alkoxy” refers to a radical formed between analkyl group and an oxygen atom wherein the oxygen atom is used to attachthe alkoxy group to a parent molecule. Alkoxy groups as used herein mayoptionally include further substituent groups. Particular alkoxy groupsinclude, by way of example, substituted or unsubstituted methoxy,substituted or unsubstituted ethoxy, substituted or unsubstitutedn-propoxy, substituted or unsubstituted isopropoxy, substituted orunsubstituted n-butoxy, substituted or unsubstituted tert-butoxy,substituted or unsubstituted sec-butoxy, substituted or unsubstitutedn-pentoxy, substituted or unsubstituted n-hexoxy, substituted orunsubstituted 1,2-dimethylbutoxy, and the like.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon chain radical containing up to twenty four carbon atoms andhaving at least one carbon-carbon double bond. Alkenyl groups as usedherein may optionally include one or more further substituent groups.Particular alkenyl groups include substituted or unsubstituted ethenyl(—CH═CH2), substituted or unsubstituted n-propenyl (—CH2CH═CH2),substituted or unsubstituted isopropenyl (—C(CH3)=CH2), substituted orunsubstituted vinyl and substituted vinyl, and the like.

As used herein, the term “aryl” refers to a mono- or polycycliccarbocyclic ring system radicals having one or more aromatic rings. Arylgroups as used herein may optionally include further substituent groups.Typical aryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like, and may be substituted or unsubstituted.Particularly, an aryl group comprises from 6 to 14 carbon atoms.

“Alkaryl” refers to an aryl group, as defined above, substituted withone or more substituted or unsubstituted alkyl groups, as defined above.

“Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above,substituted with one or more substituted or unsubstituted aryl groups,as defined above.

“Aryloxy” refers to substituted or unsubstituted —O-aryl groups wherein“aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR28R29, wherein each of R28 andR29 are independently selected from hydrogen and substituted orunsubstituted alkyl.

“Arylamino” refers to the group aryl-NR30R31, wherein each of R30 andR31 are independently selected from hydrogen, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl.

“Alkoxyamino” refers to a radical —N(H)OR32 where R32 represents asubstituted or unsubstituted alkyl or substituted or unsubstitutedcycloalkyl group as defined herein.

“Alkoxycarbonyl” refers to a substituted or unsubstituted radical—C(O)-alkoxy where alkoxy is as defined herein.

“Alkylarylamino” refers to a substituted or unsubstituted radical—NR33R34 where R33 represents an alkyl or cycloalkyl group and R34 is anaryl as defined herein.

“Alkylsulfonyl” refers to a substituted or unsubstituted radical—S(O)2R35 where R35 is an alkyl or cycloalkyl group as defined herein.Representative examples include, but are not limited to, methylsulfonyl,ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.

“Alkylsulfinyl” refers to a substituted or unsubstituted radical—S(O)R35 where R35 is an alkyl or cycloalkyl group as defined herein.Representative examples include, but are not limited to, methylsulfinyl,ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.

“Alkylthio” refers to a substituted or unsubstituted radical —SR35 whereR35 is an alkyl or cycloalkyl group as defined herein that may beoptionally substituted as defined herein. Representative examplesinclude, but are not limited to, methylthio, ethylthio, propylthio,butylthio, and the like.

“Amino” refers to the radical —NH2.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R36)2where each R36 is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,and where both R groups are joined to form an alkylene group. When bothR groups are hydrogen, —N(R36)2 is an amino group.

“Aminocarbonyl” refers to the group —C(O)NR37R37 where each R37 isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aryl and substituted or unsubstituted cycloalkyl, orwhere the R37 groups are joined to form an alkylene group.

“Aminocarbonylamino” refers to the group —NR38C(O)NR38R38 where each R38is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted aryl or substituted or unsubstitutedcycloalkyl, or where two R groups are joined to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC(O)NR39R39 where each R39 isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aryl or substituted or unsubstituted cycloalkyl, orwhere the R groups are joined to form an alkylene group.

“Arylalkyloxy” refers to a substituted or unsubstituted —O-arylalkylradical where arylalkyl is as defined herein.

“Arylamino” means a substituted or unsubstituted radical —NHR40 whereR40 represents an aryl group as defined herein.

“Aryloxycarbonyl” refers to a substituted or unsubstituted radical—C(O)—O-aryl where aryl is as defined herein.

“Arylsulfonyl” refers to a r substituted or unsubstituted radical—S(O)2R41 where R41 is an aryl or heteroaryl group as defined herein.

“Azido” refers to the radical —N3.

“Bicycloaryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent bicycloaromatic ring system. Typical bicycloaryl groups include,but are not limited to, groups derived from indane, indene, naphthalene,tetrahydronaphthalene, and the like, and may be substituted orunsubstituted. Particularly, an aryl group comprises from 8 to 11 carbonatoms.

“Bicycloheteroaryl” refers to a monovalent bicycloheteroaromatic groupderived by the removal of one hydrogen atom from a single atom of aparent bicycloheteroaromatic ring system. Typical bicycloheteroarylgroups include, but are not limited to, groups derived from benzofuran,benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline,phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole,naphthyridine, benzoxadiazole, pteridine, purine, benzopyran,benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine,quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline,and the like, and may be substituted or unsubstituted. Preferably, thebicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with5-10 membered heteroaryl being particularly preferred. Particularbicycloheteroaryl groups are those derived from benzothiophene,benzofuran, benzothiazole, indole, quinoline, isoquinoline,benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” refers to the radical —C(O)N(R42)2 where each R42 group isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl or substituted or unsubstituted aryl, asdefined herein, which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Carboxyamino” refers to the radical —N(H)C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like, and may be substituted orunsubstituted.

“Cycloalkoxy” refers to the group —OR43 where R43 is substituted orunsubstituted cycloalkyl. Such cycloalkoxy groups include, by way ofexample, substituted or unsubstituted cyclopentoxy, substituted orunsubstituted cyclohexoxy and the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as substituted or unsubstituted cyclohexenyl, substituted orunsubstituted cyclopentenyl, substituted or unsubstituted cyclopropenyl,and the like.

“Fused Cycloalkenyl” refers to a substituted or unsubstitutedcycloalkenyl having two of its ring carbon atoms in common with a secondaliphatic or aromatic ring and having its olefinic unsaturation locatedto impart aromaticity to the cycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NR44R45 where R44 and R45 independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine, chlorine, bromine, and iodine.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-15 membered heteroaryl, with 5-10 membered heteroarylbeing particularly preferred. Particular heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R46, —O—, ═O,—OR46, —SR46, —S—, ═S, —NR46R47, ═NR46, —CX3, —CF3, —CN, —OCN, —SCN,—NO, —NO2, ═N2, —N3, —S(O)2O-, —S(O)2OH, —S(O)2R46, —OS(O2)O—,—OS(O)2R46, —P(O)(O—)₂, —P(O)(OR46)(O—), —OP(O)(OR46)(OR47), —C(O)R46,—C(S)R46, —C(O)OR46, —C(O)NR46R47, —C(O)O—, —C(S)OR46, —NR48C(O)NR46R47,—NR48C(S)NR46R47, —NR49C(NR48)NR46R47 and —C(NR48)NR46R47, where each Xis independently a halogen; each R46, R47, R48 and R49 are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl,substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR50R51, —C(O)R50 or —S(O)2R50 or optionally R50 andR51 together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R50 and R51are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedalkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

“Benzaldehyde” refers to an aryl group substituted with a formyl groupor radical (i.e. —C(O)H). Examples of representative substitutedbenzaldehydes (Formula I) and the hemiacetal (Formula II) and acetal(Formula III) equivalents include the following:

wherein each R₁, R₂, R₃, R₄, and R₅ is independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, cycloalkyl,cycloheteroalkyl, alkoxy, alkoxyamino, alkoxycarbonyl, cycloalkoxy,cycloalkenyl, cyano, cyanato, aryl, arylalkyl, alkylaryl, aryloxy,heteroaryl, heteroaryloxy, amino, aminoalkyl, alkylarylamino,alkylamino, aminocarbonylamino, aminocarbonyloxy, arylamino, azido,bicycloaryl, carbamoyl, carboxy, carboxyamino, heteroarylamino,alkylsulfonyl, alkyl thio, and sulfone;

wherein at least one of R₁, R₂, R₃, R₄, or R₅ is not hydrogen; and eachR₆ is independently alkyl.

“Pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

“Cosmetically acceptable” means suitable for cosmetic applications,including topical application of the compositions disclosed herein inthe absence of significant adverse side effects upon application of thecomposition or compounds disclosed herein. Other applications includeskin care applications, including but not limited to lotions, cream,cleansing creams or lotions, soaps and other cleansers, antiperspirantand/or deodorants, makeup products, such as face powders, foundations,rouge, eye shadow, mascara, eyeliner or lipstick, sun protectionproducts, such as sunscreen or other UV-protective cosmetics, lotions orcreams, hairdressing products, such as shampoo, rinses, or treatmentsetting agents. The phrases “pharmaceutically acceptable” and“cosmetically acceptable” are not meant to imply mutual exclusiveness inall applications. In some embodiments, a composition may be both“pharmaceutically acceptable” and “cosmetically acceptable,” dependentupon the need and course of action of the compositions disclosed herein.

“Pharmaceutically acceptable salt” refers to a salt of a compounddisclosed herein that is pharmaceutically acceptable and that possessesthe desired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. In some embodiments, a“pharmaceutically acceptable salt” may also be used in conjunction withcosmeceutically-acceptable compositions.

The term “pharmaceutically acceptable cation” refers to a non toxic,acceptable cationic counter-ion of an acidic functional group. Suchcations are exemplified by sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium cations, and the like. In some embodiments,a “pharmaceutically acceptable cation” may also be used in conjunctionwith cosmeceutically-acceptable compositions.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a disclosed compound is administered. Insome embodiments, a “pharmaceutically acceptable vehicle” may also beused in conjunction with cosmetically-acceptable compositions.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrugs” refers to compounds, including derivatives of disclosedcompounds, which have cleavable groups and become by solvolysis or underphysiological conditions of compounds which are pharmaceutically activein vivo. Such examples include, but are not limited to, choline esterderivatives and the like, N-alkylmorpholine esters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. Conventional solvents includewater, ethanol, acetic acid and the like. The compounds disclosed hereinmay be prepared e.g. in crystalline form and may be solvated orhydrated. Suitable solvates include pharmaceutically acceptablesolvates, such as hydrates, and further include both stoichiometricsolvates and non-stoichiometric solvates.

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Effective amount” means the amount of a compound that, whenadministered to a subject for treating a disease, cosmetic ordermatological condition, is sufficient to effect such treatment for thedisease, cosmetic or dermatological condition. The “effective amount”can vary depending on the compound, the disease and its severity, andthe age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder, or even preventing the same. In astill further embodiment, “treating” or “treatment” refers toadministration of the compound or compositions disclosed herein forcosmetic purposes.

Other derivatives of the disclosed compounds have activity in both theiracid and acid derivative forms, but in the acid sensitive form oftenoffers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives such as, for example, esters prepared by reaction ofthe parent acid with a suitable alcohol, or amides prepared by reactionof the parent acid compound with a substituted or unsubstituted amine,or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromaticesters, amides and anhydrides derived from acidic groups pendant on thedisclosed compounds are preferred prodrugs. In some cases it isdesirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or ((alkoxycarbonyl)oxy)alkylesters. Preferred are the C1 to C8alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12arylalkyl esters of the disclosed compounds herein.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be 2H/D, any carbon may be 13C, orany nitrogen may be 15N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, thedisclosed compounds may include the preparation of isotopic variantswith radioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as11C, 18F, 15O and 13N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the contemplatedcompounds.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of it electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The disclosed compounds may possess one or more asymmetric centers; suchcompounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art.

Melanin Disorders

As discussed above, melanin in humans is the primary determinant of skincolor. Melanin pigments (eumelanin, pheomelanin and neuromelanin) arederivatives of the amino acid tyrosine, and production of melaninpigments is catalysed by the enzyme tyrosinase. Melanin is also found inhair, the pigmented tissue underlying the iris of the eye, as well asthe stria vascularis of the inner ear. Melanin disorders can thus affecta variety of physiological systems, including the skin, hair, eye, innerear, as well as neurological structures in the brain, where tissues withmelanin include the medulla and zona reticularis of the adrenal gland,and pigment-bearing neurons within areas of the brainstem, such as thelocus coeruleus and the substantia nigra.

Environmental and/or physiological stress can cause disorders in melaninproduction, as well as various genetic abnormalities. With regards tohypopigmentation disorders, there are approximately ten different typesof oculocutaneous albinism, which is mostly an autosomal recessivedisorder. Hypopigmentation occurs when pigment-producing cells(melanocytes) are either destroyed or inactive. Other hypopigmentationdisorders include conditions due to skin damage (e.g. burn or ablativelaser resurfacing) or due to autoimmune disease where the immune systemattacks melanocytes, as in vitiligo. Vitiligo can also be caused byphysical trauma or certain diseases, such as Addison's disease ordiabetes.

Hyperpigmentation or hypermelanosis disorders result in an increase inmelanin or melanocyte production and/or distribution. For example,post-inflammatory hyperpigmentation (“PIH”) represents the sequelae ofvarious cutaneous disorders, including infections, allergic reactions,mechanical injuries, reactions to medications, phototoxic eruptions,trauma (e.g. burns), as well as reactions to devices, includingelectromagnetic devices such as ultrasound, radiofrequency, lasers,light-emitting diodes and visible light therapy, as well asmicrodermabrasion reactions, shaving, chemical peels or otherdermatological procedures. PIH occurs widely in the human population andcan be the source of significant psychosocial distress for thoseaffected with this disorder. PIH may occur as a pathophysiologicresponse to cutaneous inflammation. Melanocytes can be stimulated by theinflammatory process to synthesize and secrete more melanin frommelanocytes, or the number of melanocytes can increase in the epidermis,leading to hyperpigmentation of the skin. PIH can also occur wheninflammation succeeds in disrupting the basal cell layer, causingmelanin pigment to be released and subsequently trapped by macrophagesin the papillary dermis. PIH also occurs in instances where inflammationis untreated. One example of PIH as a result of inflammation is acnescarring. Hyperpigmentation or hypermelanosis disorders due toenvironmental stressors, such as hormonal imbalance, can also affectmelanin or pigmentation levels in the skin. Other hyperpigmentationdisorders include café au lait macules, melasma, choasma, age spots,drug-induced hyperpigmentation, Addison's disease, epheides (freckles),seborrheic keratosis, acanthosis nigricans, solar lentigines (sunspots), photoxic/photoallergic reaction, hemochromatosis and diabeticdermopathy.

Current treatment of hyperpigmentation disorders include topicallightening agents, laser/intense pulsed light, cryotherapy and chemicalpeels. However, for many individuals, cosmetic camouflaging of hyper orhypopigmentation cutaneous manifestations is the only viablealternative. Effective treatment of hypo and hyperpigmentationdisorders, therefore, is needed.

The compositions disclosed herein seek to treat melanin disorders,including PIH and other hyperpigmentation disorders by modifying melanindistribution and/or production.

The compositions disclosed herein also seek to treat melanin disordersin conjunction with treatments and/or procedures that may causehypermelanosis or hyperpigmentation disorders. Accordingly, thecompositions disclosed herein may be used in conjunction with thetreatment of skin disorders or trauma as a result of a mechanical injuryor therapy, including but not limited to laser treatment, chemicalpeels, intense pulsed light, dermabrasion or cryotherapy.

Compounds

Disclosed herein are compositions comprising substituted benzaldehydes,at least one or a blend of pharmaceutically or cosmetically activeagents, and a pharmaceutically or cosmetically acceptable carrier. Insome embodiments, the substituted benzaldehydes disclosed herein areused in combination with at least one additional therapeutic agent.

In some embodiments, the composition comprises a substitutedbenzaldehyde of Formula I:

wherein each R₁, R₂, R₃, R₄, and R₅ is independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, aryloxy, cycloalkyl,cycloheteroalkyl, alkoxy, alkoxyamino, alkoxycarbonyl, cycloalkoxy,cycloalkenyl, cyano, cyanato, aryl, arylalkyl, alkylaryl, aryloxy,heteroaryl, heteroaryloxy, amino, aminoalkyl, alkylarylamino,alkylamino, aminocarbonylamino, aminocarbonyloxy, arylamino, azido,bicycloaryl, carbamoyl, carboxy, carboxyamino, heteroarylamino,alkylsulfonyl, alkyl thio, and sulfone; and wherein at least one of R₁,R₂, R₃, R₄, or R₅ is not hydrogen.

In specific embodiments, R3 is ethoxy. In other embodiments, R1, R2, R4,and R5 are hydrogen.

Specific compounds of Formula I are shown below:

Non-limiting examples of substituted benzaldehydes includealkoxy-substituted benzaldehydes (e.g., 4-ethoxybenzaldehyde,2-ethoxybenzaldehyde, 2-acetoxy-3-methoxybenzaldehye,4-allyloxybenzaldehyde, 4-propoxybenzaldehyde, 4-butoxtbenzaldehyde,2-fluoro-4-ethoxybenzaldehyde), amino-substituted benzaldehydes,alkyl-substituted benzaldehydes, aryl-substituted benzaldehydes, andsulfone-substituted benzaldehydes. In one embodiment, the substitutedbenzaldehyde is 4-ethoxybenzaldehyde, 2-ethoxybenzaldehyde,4-allyloxybenzaldehyde and/or 4-propoxybenzaldehyde. In one particularembodiment, the substituted benzaldehyde is 4-ethoxybenzaldehyde.

In certain embodiments, the substituted benzaldehyde compounds includetheir acetal and hemiacetal equivalents (i.e., ^(˜)C(OR₆)(OH) and^(˜)C(OR₆)₂ replaces the formyl group or ^(˜)C(O)H of the benzaldehyde,wherein R is an alkyl group). In some embodiments, the compositioncomprises the hemiacetal of Formula II:

wherein each R₁, R₂, R₃, R₄, and R₅ is independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, cycloalkyl,cycloheteroalkyl, alkoxy, alkoxyamino, alkoxycarbonyl, cycloalkoxy,cycloalkenyl, cyano, cyanato, aryl, arylalkyl, alkylaryl, aryloxy,heteroaryl, heteroaryloxy, amino, aminoalkyl, alkylarylamino,alkylamino, aminocarbonylamino, aminocarbonyloxy, arylamino, azido,bicycloaryl, carbamoyl, carboxy, carboxyamino, heteroarylamino,alkylsulfonyl, alkyl thio, and sulfone;

wherein at least one of R₁, R₂, R₃, R₄, or R₅ is not hydrogen; and eachR₆ is independently alkyl.

In other embodiments, the composition comprises the acetal of FormulaIII:

wherein each R₁, R₂, R₃, R₄, and R₅ is independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, acyloxy, cycloalkyl,cycloheteroalkyl, alkoxy, alkoxyamino, alkoxycarbonyl, cycloalkoxy,cycloalkenyl, cyano, cyanato, aryl, arylalkyl, alkylaryl, aryloxy,heteroaryl, heteroaryloxy, amino, aminoalkyl, alkylarylamino,alkylamino, aminocarbonylamino, aminocarbonyloxy, arylamino, azido,bicycloaryl, carbamoyl, carboxy, carboxyamino, heteroarylamino,alkylsulfonyl, alkyl thio, and sulfone;

wherein at least one of R₁, R₂, R₃, R₄, or R₅ is not hydrogen; and eachR₆ is independently alkyl.

Additional Active Agents

In one embodiment, the composition further comprises an activeingredient. Suitable active ingredients include, but are not limited tobotanicals, nutraceuticals, cosmeceuticals, therapeutics,pharmaceuticals, antimicrobials, steroidal hormones, antidandruffagents, anti-acne components, sunscreens, sunblocks, sunprotectants,antibiotics, antivirals, antifungals, steroids, analgesics, antitumordrugs, investigational drugs, skin conditioning agents, or any compoundswhich would result in a complimentary or synergistic combination withthe factors in the metabolized conditioned media or metabolized cellextract.

In a further embodiment, also included are topical formulations thatcomprise a composition for cosmetic or dermatological use, whichcomposition comprises a cosmetically and/or dermatologically effectiveamount of the combination stated above, wherein the like acting agent isa cosmetically active agent. More particularly, the like-acting agent isa skin lightening or skin bleaching compound. In some embodiments, theskin lightening or skin bleaching compound is hydroquinone, kojic acid,ascorbic acid, magnesium ascorbyl phosphate or ascorbyl glucosamine, ormixtures thereof.

In another embodiment of the combination described above, the additionalpharmaceutical or cosmetic agent is a skin care active agent. In someembodiments, the skin care active agent is an abrasive, an absorbent, anastringent, an aesthetic component, such as fragrances, pigments,colorings/colorants, essential oils, skin sensates, astringents andother aesthetic components, an antioxidant, a free-radical scavengingagent, a reducing agent, a sequestrant, a skin bleaching or lighteningagent, a skin conditioning agent, for example humectants and emollients,a skin soothing agent, a skin healing agent, such as pathenol andderivatives, aloe vera, pantothenic acid, allantoin, bisbolol,dipotassium glycyrrhizinate, skin treating agents, vitamins andderivatives, such as a retinoid, or mixtures thereof. In someembodiments, the retinoid is retinol, retinal, retinol esters, retinylpropionate, retinoic acid, retinyl palmitate, or mixtures thereof.

In other embodiments, the composition comprises one or moreantioxidant(s). Non-limiting examples of antioxidants are selected fromthe group consisting of niacinamide, vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, genistein, andpycnogenol. Other embodiments include phenols and phenolic acids(guaiacol, hydroquinone, vanillin, gallic acids and their esters,protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylicacid, nordihydroguaiaretic acid (NDGA), eugenol); curcumins, tocopherols(including tocopherols (alpha, beta, gamma, delta) and theirderivatives, such as tocopheryl-acylate (e.g., -acetate, -laurate,myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitabletocopheryl-lipoate), tocopheryl-POE-succinate; Dunaliella SalinaExtract; trolox and corresponding amide and thiocarboxamide analogues;ascorbic acid and its salts, isoascorbate, alkylascorbic acids, ascorbylesters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, orlinoleoyl-L-ascorbic acid, etc.). Also useful are oxidized compounds,such as sodium bisulphite, sodium metabisulphite, thiourea; chelatingagents, such as EDTA (e.g., disodium EDTA), EGTA, desferral;transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion,heamopexin, albumin, glucose, ubiquinol-10; enzymatic antioxidants, suchas superoxide dismutase and metal complexes with a similar activity,including catalase, glutathione peroxidase, and less complex molecules,such as beta-carotene, bilirubin, uric acid; flavonoids (flavones,flavonols, flavonones, flavanonals, chacones, anthocyanins),N-acetylcystein, mesna, glutathione, thiohistidine derivatives,triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and theiresters (coumaric acids and esters, caffeic acid and their esters,ferulic acid, (iso-) chlorogenic acid, sinapic acid). Also included areextracts, including but not limited to plant extracts or cell extractscontaining antioxidants, including grape seed extract, pomegranateextract, spice extracts (e.g., from clove, cinnamon, sage, rosemary,mace, oregano, allspice, nutmeg); oat flour extracts, such asavenanthramide 1 and 2; thioethers, dithioethers, sulphoxides,tetralkylthiuram disulphides and extracts from other plant derivedmaterial. Also included is carnosic acid, carnosol, carsolic acid;rosmarinic acid, rosmaridiphenol, gentisic acid, ferulic acid; phyticacid, steroid derivatives (e.g., U74006F); tryptophan metabolites (e.g.,3-hydroxykynurenine, 3-hydroxyanthranilic acid), andorganochalcogenides.

In other embodiments, the composition comprises at least one additionalskin lightening agent. Non-limiting examples of skin-lightening agentsare selected from the group of hydroquinone, licorice extract (e.g.,Glycyrrhiza Glabra (licorice) root extract), an alpha MSH antagonist(e.g. undecylenoyl phenylalanine), phytic acid, monobenzyl ether ofhydroquinone, azelaic acid, kojic acid, mequinol, retinoids (e.g.,tretinoin, adapalene), soy proteins, alpha-hydroxy acids (e.g., glycolicacid), trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, and tranexamincacid.

In other embodiments, the composition comprises at least one botanicalingredient and/or extract. Non-limiting examples of botanical extractsare selected from the group arbutin, alpha-arbutin, deoxyarbutin,aloesin, flavonoids, isoflavones (e.g., 6,7,4′-trihydroxyisoflavone,glycitein, daidzein, genistein), flavonones (e.g., hesperidin,eriodictyol, and naringenin), flavonols, p-coumaric acid, gentisic acid,licorice extracts (e.g., glabridin, liquiritin, glabrene,isoliquiritigenin licuraside, isoliquiritin, licochalcone A),niacinamide, yeast derivatives, polyphenols, (e.g., proanthocyanidins,procyanidins, ellagic acid), ammonium glycyrrhizinate, icariin, piceid,salidroside, epigallocatechin-3-gallate, glycyrrhiza cinnamic aid,cinnamic acid, sophorcarpidine, aloe vera extract, alaria esculentaextract, alfalfa extract, algae extract, althaea extract, angelicaextract, apple extract, arnica extract, ascorbyl palmitate, avocado oil,babassu palm tree fruit, balm mint extract, bamboo extract, bergamotoil, betula extract, bilberry, birch leaf extract, bisabolol,blackcurrant extract, black raspberry seed oil, bladderwrack extract,blue-green algae, blue malva extract, borage seed oil, boswelliaserrata, buddleja davidii extract, buckthorn, buckwheat seed extract,burdock root extract, burdock, butcher's broom, calendula, calendulaextract, camellia oil, capsaicin, carrageenan extract, carrot extract,cascara sagrada, castor oil, cayenne, cedarwood, chamomile, chamomileextract, chamomile oil, chaparral extract, chaste tree berry extract,chia seed oil, chickpea seed extract, chlorella, chrysanthellis,cinnamon bark, citrus extract, clover, clover blossom extract, cloverextract, clover flower oil, cocoa extract, cocoa seed butter,codonopsis, coleus forskohlli, coriander, corn oil, cottonseed oil,couch grass, crambe abyssinica seed extract, cranberry protein, crithmummaritimum extract, cupuacu, cypress oil, dandelion, dandelion extract,dong quai, Dunaliella Salina extract, Echinacea angustifolia purpurea,echium plantagineum, elderberry, esculin, eucalyptus, evening primroseoil, fennel, ferula foetida root extract, flaxseed oil, fucoidanextract, garcinia cambogia, garlic, geranium extract, geranium oil,ginger, ginger root extract, ginkgo biloba, ginseng, ginseng extract,glucosamine, golden seal extract, gotu kola, grapefruit extract,grapeseed, grapeseed extract, grapeseed oil, green tea, green teaextract, guarana, guggul gum extract, gymnesa sylvestre, hazel oil,hawthorn, holarrhena antidysenterica extract, honeysuckle extract, hopsextract, horse chestnut, horsetail extract, hybrid safflower oil,hydrolyzed soy protein, imperata cylindrical root extract, ivy leafextract, jasmine oil, jojoba oil, juniper oil, kelp, kiwi seed fruitoil, kukui nut oil, lactic acid, lactospore, laminaria digitata,lavandin oil, lavender, lavender oil, lavender extract, L-carnitine,lecithin, lemon balm, lemon extract, lemon fruit extract, lemon oil,lemon verbena botanical plant essence, lemongrass extract, licoriceextract (e.g., Glycyrrhiza Glabra (licorice) root extract), lime oil,linden extract, lycium barbarum fruit extract, lysate extract, lysine,maca root, macadamia oil, magnesium ascorbyl phosphate, Mahoniumaquifolium (Oregon grape root) extract, maitake extract, mallow extract,maracuja, marrubium vulgare extract, marshmallow, manila oil, matricariaoil, meadowsweet. Melissa extract, menthol, milk thistle, moms alba rootextract, mulberry extract (e.g., mulberroside F, gallic acid, quercetin,linoleic acid, palmitic acid), nettle extract, nettle root, nori sealettuce, nutmeg oil, oat amino acids, oat extract, oat kernel meal,oligophycocorail (sea algae) extract, olive oil, olive leaf extract,squalene (e.g., olive squalen), orange blossom, orange oil, orange fruitextract, orange peel extract, orchid extract, panax ginseng extract,pansy extract, panthenol, papaya enzyme, passion fruit oil, patchoulioil, pea extract, pea protein, peach extract, peanut oil, pecan oil,pepper, peppermint, peppermint oil, perilla seed oil, pine leaf oil,pineapple enzyme, plankton extract, plantain extract, polygonumfagopyrum seed extract, pomegranate extract, pomegranate seed oil,portulaca extract, psyllium, pumpkin seed oil, raspberry extract, redclover, red clover extract, red marine algae extract, reishii,resveratrol, retinyl palmitate, rice bran oil, rhodiola, rhubarb, riceprotein, Rosa roxburghii fruit extract, rose geranium botanical plantessence, rosehip extract, rosemary, sccharomyces boulardii, saffloweroil, sage, sage extract, sambucus Canadensis extract, sandalwood,turmeric (Curcuma longa root) extract, Bulbine frutescens extract,Bulbine frutescens gel, and phytessence wakame (sea kelp).

In yet other embodiments, the composition comprises at least onesunscreen, sunprotectant or sunblock agent. “Sunscreen”, “sunprotectant”or “sunblock” as used herein defines ultraviolet ray-blocking compoundsexhibiting absorption or blockage within the wavelength region betweenabout 290 and 420 nm. Such agents may be classified into five groupsbased upon their chemical structure: para-amino benzoates; salicylates;cinnamates; benzophenones; and miscellaneous chemicals including menthylanthralinate and digalloyl trioleate. Inorganic sunscreens may also beused including titanium dioxide, zinc oxide, iron oxide and polymerparticles such as those of polyethylene and polyamides. Specificsuitable sunscreen agents include, for example: p-aminobenzoic acid, itssalts and its derivatives (ethyl, isobutyl, glyceryl esters;p-dimethylaminobenzoic acid); Anthranilates (i.e., o-aminobenzoates;methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, andcyclohexenyl esters); Salicylates (amyl, phenyl, benzyl, menthyl,glyceryl, and dipropylene glycol esters); Cinnamic acid derivatives(methyl and benzyl esters, alpha-phenyl cinnamonitrile; butyl cinnamoylpyruvate); Dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); Trihydroxycinnamic acidderivatives (esculetin, methylesculetin, daphnetin, and the glucosides,esculin and daphnin); Hydrocarbons (diphenylbutadiene, stilbene);Dibenzalacetone and benzalacetophenone; Naphtholsulfonates (sodium saltsof 2-naphthol-3,3-disulfonic and of 2-naphthol-6,8-disulfonic acids);Dihydroxynaphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,7-methyl, 3-phenylyll); Diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxalole, various aryl benzothiazoles); Quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- ormethoxy substituted benzophenones; Uric and vilouric acids; Tannic acidand its derivatives (e.g., hexaethylether); (Butyl carbityl) (6-propylpiperonyl)ether; Hydroquinone; Benzophenones (Oxybenzene, Sulisobenzone,Dioxybenzone, Benzoresorcinol, 2,2′,4,4′-Tetrahydroxybenzophenone,2,2′-Dihydroxy-4,4′-dimethoxybenzophenone, Octabenzone;4-Isopropyhldibenzoylmethane; Butylmethoxydibenzoylmethane; Etocrylene;and 4-isopropyl-di-benzoylmethane; titanium dioxide, iron oxide, zincoxide, and mixtures thereof. Other cosmetically-acceptable sunscreensand concentrations (percent by weight of the total cosmetic sunscreencomposition) include diethanolamine methoxycinnamate (10% or less),ethyl-[bis(hydroxypropyl)]aminobenzoate (5% or less), glycerylaminobenzoate (3% or less), 4-isopropyl dibenzoylmethane (5% or less),4-methylbenzylidene camphor (6% or less), terephthalylidene dicamphorsulfonic acid (10% or less), and sulisobenzone (also calledbenzophenone-4, 10% or less). Yet other cosmetically-acceptablesunscreens and concentrations (reported as a percentage by weight of thetotal cosmetic sunscreen composition, and referring to the finalpercentage of the sunscreen) include: aminobenzoic acid (also calledpara-aminobenzoic acid and PABA; 15% or less; a UVB absorbing organicsunscreen), avobenzone (also called butyl methoxy dibenzoylmethane; 3%or less, a UVA I absorbing organic sunscreen), cinoxate (also called2-ethoxyethyl p-methoxycinnamate; 3% or less, a UVB absorbing organicsunscreen), dioxybenzone (also called benzophenone-8; 3% or less, a UVBand UVA II absorbing organic sunscreen), homosalate (15% or less, a UVBabsorbing organic sunscreen), menthyl anthranilate (also called menthyl2-aminobenzoate; 5% or less, a UVA II absorbing organic sunscreen),octocrylene (also called 2-ethylhexyl-2-cyano-3,3 diphenylacrylate; 10%or less, a UVB absorbing organic sunscreen), octyl methoxycinnamate(7.5% or less, a UVB absorbing organic sunscreen), octyl salicylate(also called 2-ethylhexyl salicylate; 5% or less, a UVB absorbingorganic sunscreen), oxybenzone (also called benzophenone-3; 6% or less,a UVB and UVA II absorbing organic sunscreen), padimate 0 (also calledoctyl dimethyl PABA; 8% or less, a UVB absorbing organic sunscreen),phenylbenzimidazole sulfonic acid (water soluble; 4% or less, a UVBabsorbing organic sunscreen), sulisobenzone (also called benzophenone-4;10% or less, a UVB and UVA II absorbing organic sunscreen), titaniumdioxide (25% or less, an inorganic physical blocker of UVA and UVB),trolamine salicylate (also called triethanolamine salicylate; 12% orless, a UVB absorbing organic sunscreen), and zinc oxide (25% or less,an inorganic physical blocker of UVA and UVB).

In still other embodiments, the composition comprises at least oneanti-acne agent. Suitable anti-acne agents may include salicylic acid;5-octanoyl salicylic acid; resorcinol; retinoids such as retinoic acidand its derivatives; sulfur-containing D and L amino acids other thancysteine; lipoic acid; antibiotics and antimicrobials such as benzoylperoxide, octopirox, tetracycline, 2,4,4′-trichloro-2′-hydroxydiphenylether, 3,4,4′-trichlorobanilide, azelaic acid, phenoxyethanol,phenoxypropanol, phenoxisopropanol, ethyl acetate, clindamycin andmelclocycline; flavonoids; and bile salts such as scymnol sulfate,deoxycholate and cholate.

In yet still other embodiments, the composition comprises at least oneanti-inflammatory agent. Suitable anti-inflammatory agents include, butare not limited to, non-steroidal anti-inflammatory drugs such assalicylic acid, acetylsalicylic acid, methyl salicylate, aspirin,ibuprofen, naproxen, diflunisal, salsalate, olsalazine, sulfasalazine,acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen,naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine,aminopyrine, apazone and nimesulide; leukotriene antagonists including,but not limited to, zileuton, aurothioglucose, gold sodium thiomalateand auranofin; and other anti-inflammatory agents including, but notlimited to, methotrexate, colchicine, allopurinol, probenecid,sulfinpyrazone and benzbromarone. Additional anti-inflammatories usefulin topical applications include corticosteroids, such as, but notlimited to, flurandrenolide, clobetasol propionate, halobetasolpropionate, fluticasone propionate, betamethasone dipropionate,betamethasone benzoate, betamethasone valerate, desoximethasone,dexamethasone, diflorasone diacetate, mometasone furoate, amcinodine,halcinonide, fluocinonide, fluocinolone acetonide, desonide,triamcinolone acetonide, hydrocortisone, hydrocortisone acetate,fluoromethalone, prednisone, methylprednisolone, and predinicarbate.

In yet still other embodiments, the composition comprises at least oneskin conditioning agents. Suitable skin conditioning agents include, butare not limited to, butylene glycol and ethylhexylglycerin.

In one embodiment, the composition contains the following additionalactive ingredients: Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Licorice root extract, Resorcinol, and ethyl linoleate. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

Pharmaceutically or Cosmetically Suitable Carriers and Compositions

One aspect of the disclosed embodiments extends to a formulation thatcomprises a combination of a substituted benzaldehyde, additional activeagents, and a carrier. In some embodiments, the active agent is selectedfrom an antioxidant or a skin-lightening agent. In specific embodiments,the substituted benzaldehyde and active agents are administered in theform of a pharmaceutical or cosmetic composition. Such compositions canbe prepared by procedures well known in the pharmaceutical and cosmeticarts. The compositions disclosed herein can contain a cosmetically orpharmacologically acceptable carrier. Such carriers are compatible withskin, nails, mucous membranes, tissues and/or hair, and can include anyconventionally used cosmetic or pharmacological carrier. Thecompositions disclosed herein can be in any form suitable for topicalapplication, including aqueous, aqueous-alcoholic or oily solutions,lotion or serum dispersions, aqueous, anhydrous or oily gels, emulsionsobtained by dispersion of a fatty phase in an aqueous phase (O/W or oilin water) or, conversely, (W/O or water in oil), microemulsions oralternatively microcapsules, microparticles or lipid vesicle dispersionsof ionic and/or nonionic type. These compositions can be preparedaccording to conventional methods. Other than the agents disclosed, theamounts of the various constituents of the compositions are thoseconventionally used in the art. These compositions in particularconstitute protection, treatment or care creams, milks, lotions, gels orfoams for the face, for the hands, for the body and/or for the mucousmembranes, or for cleansing the skin. The compositions can also consistof solid preparations constituting soaps or cleansing bars.

In some embodiments, the compositions disclosed herein are administeredin an effective amount to treat a melanin disorder. Examples of routesof administration include, but are not limited to, oral, buccal,inhalation, intradermal, subcutaneous, transmucosal, transdermal, ortopical administration. Topical administration may also involve the useof transdermal administration such as transdermal patches oriontophoresis devices. The construction and use of transdermal patchesfor the delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patchescan be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

Pharmaceutically or cosmetically appropriate vehicles for suchformulations include, for example, lower aliphatic alcohols, polyglycols(e.g., glycerol or polyethylene glycol), esters of fatty acids, oils,fats, silicones, and the like. Such preparations can also includepreservatives (e.g., p-hydroxybenzoic acid esters) and/or antioxidants(e.g., ascorbic acid and tocopherol). See also DermatologicalFormulations: Percutaneous absorption, Barry (Ed.), Marcel Dekker Incl,1983.

In other embodiments, the composition further comprises at least one ofwater, a preservative, a surfactant, an emulsifier, a conditioner, anemollient, a wax, an oil, a polymer, a thickener (viscosity increasingagent), a fixative, a colorant, a humectant, a moisturizer, astabilizer, a diluent, a solvent and a fragrance.

In one embodiment, the composition further comprises at least onepreservative. Suitable preservatives include, but are not limited to,potassium sorbate, acids, alcohols, glycols, parabens,quaternary-nitrogen containing compounds, isothiazolinones,aldehyde-releasing compounds and halogenated compounds. Illustrativealcohols include phenoxyethanol, isopropyl alcohol, and benzyl alcohol;illustrative glycols include propylene, butylene and pentylene glycols;illustrative parabens include (also known as parahydroxybenzioc acids)methyl, propyl and butyl parabens; illustrative quaternary nitrogencontaining compounds include benzalkonium chloride, Quartenium 15;illustrative isothiazoles include methylisothiazoline,methychlorolisothiazoline; illustrative aldehyde releasing agentsinclude DMDM hydantion, imiadolidinyl urea and diazolidinyl urea;illustrative antioxidants include butylated hydroxytoluene, tocopheroland illustrative halogenated compounds include triclosan andchlorohexidene digluconate. Examples of preservatives useful for thepurpose of the present disclosure can be found in Steinberg, D.“Frequency of Use of Preservatives 2007”. Cosmet. Toilet. 117, 41-44(2002) and, “Preservative Encyclopedia” Cosmet. Toilet. 117, 80-96(2002). In addition, enzyme preservative systems such as those describedin the article by Ciccognani D. Cosmetic Preservation Using Enzymes, in“Cosmetic and Drug Microbiology”, Orth DS ed., Francis & Taylor, BocaRaton, Fla. (2006) can also be effective for use with the composition ofthe present disclosure.

In one embodiment, the composition further comprises at least oneocclusive. Suitable occlusives include, but are not limited to,capryllic/capric triglycerides, and the like.

In one embodiment, the composition further comprises at least oneemollient. Suitable emollients include, but are not limited to, cetylethylhexanoate, mineral oils, lanolin, petrolatum, capric/caprylictriglyceraldehydes, cholesterol, silicones such as dimeticone,cyclometicone, almond oil, jojoba oil, avocado oil, castor oil, sesameoil, sunflower oil, coconut oil and grape seed oil, cocoa butter, oliveoil aloe extracts, fatty acids such as oleic and stearic, fatty alcoholssuch as cetyl and hexadecyl, diisopropyl adipate, hydroxybenzoateesters, benzoic acid esters of C9-15-alcohols, isononyl iso-nonanoate,ethers such as polyoxypropylene butyl ethers and polyoxypropylene cetylethers, and C12-15-alkyl benzoates, and mixtures thereof.

In one embodiment, the composition further comprises at least one filmfomers. Suitable film fomers include, but are not limited to,polyacrylate-13, Opadry II® or similar materials, e.g., such as thosedescribed in U.S. Pat. No. 4,802,924, incorporated herein by reference,may be used as a film former.

In yet other embodiments, the compound of Formula (I) is formulated fortransdermal administration. Transdermal formulations may employtransdermal delivery devices and transdermal delivery patches and can belipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. In various embodiments, suchpatches are constructed for continuous, pulsatile, or on demand deliveryof pharmaceutical agents. In additional embodiments, the transdermaldelivery of the compounds of Formula (I) is accomplished by means ofiontophoretic patches and the like. In certain embodiments, transdermalpatches provide controlled delivery of the compounds of Formula (I). Therate of absorption may be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Alternatively,absorption enhancers are used to increase absorption. Absorptionenhancers or carriers include absorbable pharmaceutically acceptablesolvents that assist passage through the skin. For example, in oneembodiment, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. Transdermal drug delivery systems are topically administeredmedicaments and may be in the form of patches that deliver drugs forsystemic effects at a predetermined and controlled rate. The componentsof transdermal devices include: (1) polymer matrix or matrices, (2) thedrug, (3) permeation enhancers and (4) other excipients.

The polymer controls the release of the drug from the device. Usefulpolymers for transdermal devices include, but are not limited to NaturalPolymers (e.g., Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,Proteins, Gums and their derivatives, Natural rubber, Starch, etc.);Synthetic Elastomers (e.g., Polybutadieine, Hydrin rubber, Polysiloxane,Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieinerubber, Neoprene, etc.); and Synthetic Polymers (e.g., Polyvinylalcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate,Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate,Epoxy, etc.)

Solvents increase penetration possibly by enclosing the polar pathwayand/or by fluidizing lipids. Examples include water alcohols (e.g.,methanol and ethanol); alkyl methyl sulfoxides (e.g., dimethylsulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide anddimethyl formamide); pyrrolidones (e.g., 2 pyrrolidone, N-methyl,2-purrolidone); laurocapram (Azone), miscellaneous solvents (e.g.,propylene glycol, glycerol, silicone fluids, isopropyl palmitate).

Surfactants may enhance polar pathway transport, especially ofhydrophilic drugs. The ability of a surfactant to alter penetration is afunction of the polar head group and the hydrocarbon chain length.Anionic surfactants include, but are not limited to, Dioctylsulphosuccinate, Sodium lauryl sulphate, and Decodecylmethyl sulphoxide.Nonionic surfactants include, but are not limited to, Pluronic F127, andPluronic F68. Bile salts include, but are not limited to, Sodium mstaurocholate, Sodium deoxycholate, and Sodium tauroglycocholate. Othersinclude, for example, Propylene glycol-oleic acid and 1,4-butanediol-linoleic acid, urea, N,N-dimethyl-m-toluamide, calciumthioglycolat, anticholinergic agents, eucalyptol,di-o-methyl-β-cyclodextrin and soyabean casein.

The fastening of all transdermal devices to the skin has so far beendone by using a pressure sensitive adhesive which can be positioned onthe face of the device or in the back of the device and extendingperipherally. Adhesive systems should adhere to the skin aggressively,but be easily removed. They should also not leave an unwashable residueon the skin, and they should not irritate or sensitize the skin.

The face adhesive system should also be physically and chemicallycompatible with the drug, excipients and enhancers of the device ofwhich it is a part. Permeation of drug should not be affected and thedelivery of simple or blended permeation enhancers should not beaffected.

Backing membranes are flexible and they provide a good bond to the drugreservoir, prevent drug from leaving the dosage form through the top,and accept printing. Backing membranes are impermeable substances thatprotect the product during use on the skin (e.g., metallic plasticlaminate, plastic backing with absorbent pad and occlusive base plate(aluminum foil), adhesive foam pad (flexible polyurethane) withocclusive base plate (aluminum foil disc), etc.).

In addition, transdermal formulations can include additional componentssuch as, but not limited to, gelling agents, creams and ointment bases,and the like. In some embodiments, the transdermal formulation furtherincludes a woven or non-woven backing material to enhance absorption andprevent the removal of the transdermal formulation from the skin. Inother embodiments, the transdermal formulations described hereinmaintain a saturated or supersaturated state to promote diffusion intothe skin

Compositions disclosed herein may be formulated in conventional mannerusing one or more pharmaceutically or cosmetically acceptable carrierscomprising excipients and auxiliaries which facilitate processing of thesubstituted benzaldehydes and optional combination agents. Properformulation is dependent upon the route of administration chosen andstandard therapeutic practice. As used herein, the term“pharmaceutically or cosmetically acceptable carrier” means an inert,non toxic solid or liquid filler, diluent or encapsulating material, notreacting adversely with the active compound or with the subject.Suitable carriers are well known, and include water, saline, aqueousdextrose, sugar solutions, ethanol, glycols and oils, including those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil and mineral oil. In other embodiments, an agent orcombination of agents of the instant embodiments can be formulated in anoleaginous hydrocarbon base, an anhydrous absorption base, awater-in-oil absorption base, an oil-in-water water-removable baseand/or a water-soluble base. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., polysorbate-80, isopropyl myristate and sodiumlauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides,terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water,calcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and polymers such as polyethyleneglycols.

Compositions can also contain adjuvants common to the cosmetic anddermatological fields, such as hydrophilic or lipophilic gelling agents,hydrophilic or lipophilic active agents, preserving agents,antioxidants, solvents, fragrances, fillers, sunscreens, odor-absorbersand dyestuffs. The amounts of these various adjuvants are thoseconventionally used in the fields considered and, for example, are fromabout 0.01% to about 20% of the total weight of the composition.Depending on their nature, these adjuvants can be introduced into thefatty phase, into the aqueous phase and/or into the lipid vesicles.

The compositions may be in the form of tablets, capsules, skin patches,inhalers, eye drops, nose drops, ear drops, suppositories, creams,ointments, injectables, hydrogels and into any other appropriateformulation known to one of skill in the art. For oral administrationthe pharmaceutical compositions may take the form of, for example,tablets or capsules prepared by conventional means with acceptableexcipients or carriers such as binding agents (e.g., pregelatinisedmaize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc or silica);disintegrants (e.g., potato starch or sodium starch glycolae); orwetting agents (e.g., sodium lauryl sulphate). Tablets may be coatedusing methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with acceptableexcipients or carriers such as suspending agents (e.g., sorbitol syrupcellulose derivatives or hydrogenated edible fats); emulsifying agents(e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, flavoring, coloring andsweetening agents as appropriate.

Topical compositions disclosed herein may be in the form of a viscousliquid, solution, suspension, liposomal formulations, gel, jelly, cream,lotion, ointment, suppository, foam, aerosol spray aqueous or oilysuspensions or solutions, emulsions, or emulsion ointments. Topicalformulation for application to skin may include ointments, lotions,pastes, creams, gels, drops, suppositories, sprays, liquids, powders,shampoos, and transdermal patches. In one embodiment, a topicalcomposition is provided which includes a topical carrier. For example,thickeners, diluents, emulsifiers, dispersing aids or binders may beused as needed. The topical carrier is selected so as to provide thecomposition in the desired form, e.g., as a liquid, lotion, cream,paste, gel, powder, or ointment, and may be comprised of a material ofeither naturally occurring or synthetic origin. Examples of suitabletopical carriers for use herein include water, alcohols and othernontoxic organic solvents, glycerin, mineral oil, silicone, petroleumjelly, lanolin, fatty acids, vegetable oils, parabens, aloe vera, waxes,and the like.

Ointments and creams can, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and willin general also containing one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

Thickeners (viscosity increasing agents) which can be used to formpharmaceutical compositions and dosage forms include, but are notlimited to, polyacrylate-13, polyisobutene, Acetamide MEA;acrylamide/ethalkonium chloride acrylate copolymer;acrylamide/ethyltrimonium chloride acrylate/ethalkonium chlorideacrylate copolymer; acrylamides copolymer; acrylamide/sodium acrylatecopolymer; acrylamide/sodium acryloyldimethyltaurate copolymer;acrylates/acetoacetoxyethyl methacrylate copolymer;acrylates/beheneth-25 methacrylate copolymer; acrylates/C10-C30 alkylacrylate crosspolymer; acrylates/ceteth-20 itaconate copolymer;acrylates/ceteth-20 methacrylate copolymer; acrylates/laureth-25methacrylate copolymer; acrylates/palmeth-25 acrylate copolymer;acrylates/palmeth-25 itaconate copolymer; acrylates/steareth-50 acrylatecopolymer; acrylates/steareth-20 itaconate copolymer;acrylates/steareth-20 methacrylate copolymer; acrylates/stearylmethacrylate copolymer; acrylates/vinyl isodecanoate crosspolymer;acrylic acid/acrylonitrogens copolymer; adipic acid/methyl DEAcrosspolymer; agar; agarose; alcaligenes polysaccharides; algin; alginicacid; almondamide DEA; almondamidopropyl betaine; aluminum/magnesiumhydroxide stearate; ammonium acrylates/acrylonitrogens copolymer;ammonium acrylates copolymer; ammonium acryloyldimethyltaurate/vinylformamide copolymer; ammonium acryloyldimethyltaurate/VP copolymer;ammonium alginate; ammonium chloride; ammonium polyacryloyldimethyltaurate; ammonium sulfate; amylopectin; apricotamide DEA;apricotamidopropyl betaine; arachidyl alcohol; arachidyl glycol; arachishypogaea (peanut) flour; ascorbyl methylsilanol pectinate; astragalusgummifer gum; attapulgite; avena sativa (oat) kernel flour; avocadamideDEA; avocadamidopropyl betaine; azelamide MEA; babassuamide DEA;babassuamide MEA; babassuamidopropyl betaine; behenamide DEA; behenamideMEA; behenamidopropyl betaine; behenyl betaine; bentonite; butoxychitosan; caesalpinia spinosa gum; calcium alginate; calciumcarboxymethyl cellulose; calcium carrageenan; calcium chloride; calciumpotassium carbomer; calcium starch octenylsuccinate; C20-40 alkylstearate; canolamidopropyl betaine; capramide DEA;capryl/capramidopropyl betaine; carbomer; carboxybutyl chitosan;carboxymethyl cellulose acetate butyrate; carboxymethyl chitin;carboxymethyl chitosan; carboxymethyl dextran; carboxymethylhydroxyethylcellulose; carboxymethyl hydroxypropyl guar; carnitine;cellulose acetate propionate carboxylate; cellulose gum; ceratoniasiliqua gum; cetearyl alcohol; cetyl alcohol; cetyl babassuate; cetylbetaine; cetyl glycol; cetyl hydroxyethylcellulose; chimyl alcohol;cholesterol/HDI/pullulan copolymer; cholesteryl hexyl dicarbamatepullulan; citrus aurantium dulcis (orange) peel extract; cocamide DEA;cocamide MEA; cocamide MIPA; cocamidoethyl betaine; cocamidopropylbetaine; cocamidopropyl hydroxysultaine; coco-betaine;coco-hydroxysultaine; coconut alcohol; coco/oleamidopropyl betaine;coco-Sultaine; cocoyl sarcosinamide DEA; cornamide/cocamide DEA;cornamide DEA; croscarmellose; crosslinked bacillus/glucose/sodiumglutamate ferment; cyamopsis tetragonoloba (guar) gum; decyl alcohol;decyl betaine; dehydroxanthan gum; dextrin; dibenzylidene sorbitol;diethanolaminooleamide DEA; diglycol/CHDM/isophthalates/SIP copolymer;dihydroabietyl behenate; dihydrogenated tallow benzylmonium hectorite;dihydroxyaluminum amino acetate; dimethicone/PEG-10 crosspolymer;dimethicone/PEG-15 crosspolymer; dimethicone propyl PG-betaine;dimethylacrylamide/acrylic acid/polystyrene ethyl methacrylatecopolymer; dimethylacrylamide/sodium acryloyldimethyltauratecrosspolymer; disteareth-100 IPDI; DMAPA acrylates/acrylicacid/acrylonitrogens copolymer; erucamidopropyl hydroxysultaine;ethylene/sodium acrylate copolymer; gelatin; gellan gum; glycerylalginate; glycine soja (soybean) flour; guar hydroxypropyltrimoniumchloride; hectorite; hyaluronic acid; hydrated silica; hydrogenatedpotato starch; hydrogenated tallow; hydrogenated tallowamide DEA;hydrogenated tallow betaine; hydroxybutyl methylcellulose; hydroxyethylacrylate/sodium acryloyldimethyl taurate copolymer;hydroxyethylcellulose; hydroxyethyl chitosan; hydroxyethylethylcellulose; hydroxyethyl stearamide-MIPA;hydroxylauryl/hydroxymyristyl betaine; hydroxypropylcellulose;hydroxypropyl chitosan; hydroxypropyl ethylene diamine carbomer;hydroxypropyl guar; hydroxypropyl methylcellulose; hydroxypropylmethylcellulose stearoxy ether; hydroxypropyl starch; hydroxypropylstarch phosphate; hydroxypropyl xanthan gum; hydroxystearamide MEA;isobutylene/sodium maleate copolymer; isostearamide DEA; isostearamideMEA; isostearamide mIPA; isostearamidopropyl betaine; lactamide MEA;lanolinamide DEA; lauramide DEA; lauramide MEA; lauramide MIPA;lauramide/myristamide DEA; lauramidopropyl betaine; lauramidopropylhydroxysultaine; laurimino bispropanediol; lauryl alcohol; laurylbetaine; lauryl hydroxysultaine; lauryl/myristyl glycol hydroxypropylether; lauryl sultaine; lecithinamide DEA; linoleamide DEA; linoleamideMEA; linoleamide MIPA; lithium magnesium silicate; lithium magnesiumsodium silicate; macrocystis pyrifera (kelp); magnesium alginate;magnesium/aluminum/hydroxide/carbonate; magnesium aluminum silicate;magnesium silicate; magnesium trisilicate; methoxy PEG-22/dodecyl glycolcopolymer; methylcellulose; methyl ethylcellulose; methylhydroxyethylcellulose; microcrystalline cellulose; milkamidopropylbetaine; minkamide DEA; minkamidopropyl betaine; MIPA-myristate;montmorillonite; Moroccan lava clay; myristamide DEA; myristamide MEA;myristamide MIPA; myristamidopropyl betaine; myristamidopropylhydroxysultaine; myristyl alcohol; myristyl betaine; natto gum;nonoxynyl hydroxyethylcellulose; oatamide MEA; oatamidopropyl betaine;octacosanyl glycol isostearate; octadecene/MA copolymer; oleamide DEA;oleamide MEA; oleamide MIPA; oleamidopropyl betaine; oleamidopropylhydroxysultaine; oleyl betaine; olivamide DEA; olivamidopropyl betaine;oliveamide MEA; palmamide DEA; palmamide MEA; palmamide MIPA;palmamidopropyl betaine; palmitamide DEA; palmitamide MEA;palmitamidopropyl betaine; palm kernel alcohol; palm kernelamide DEA;palm kernelamide MEA; palm kernelamide MIPA; palm kernelamidopropylbetaine; peanutamide MEA; peanutamide MIPA; pectin; PEG-800;PEG-crosspolymer; PEG-150/decyl alcohol/SMDI copolymer; PEG-175diisostearate; PEG-190 distearate; PEG-15 glyceryl tristearate; PEG-140glyceryl tristearate; PEG-240/HDI copolymer bis-decyltetradeceth-20ether; PEG-100/IPDI copolymer; PEG-180/laureth-50/TMMG copolymer;PEG-10/lauryl dimethicone crosspolymer; PEG-15/lauryl dimethiconecrosspolymer; PEG-2M; PEG-5M; PEG-7M; PEG-9M; PEG-14M; PEG-20M; PEG-23M;PEG-25M; PEG-45M; PEG-65M; PEG-90M; PEG-115M; PEG-160M; PEG-180M;PEG-120 methyl glucose trioleate; PEG-180/octoxynol-40/TMMG copolymer;PEG-150 pentaerythrityl tetrastearate; PEG-4 rapeseedamide;PEG-150/stearyl alcohol/SMDI copolymer; phaseolus angularis seed powder;polianthes tuberosa extract; polyacrylate-3; polyacrylic acid;polycyclopentadiene; polyether-1; polyethylene/isopropyl maleate/MAcopolyol; polyglyceryl-3 disiloxane dimethicone; polyglyceryl-3polydimethylsiloxyethyl dimethicone; polymethacrylic acid;polyquaternium-52; polyvinyl alcohol; potassium alginate; potassiumaluminum polyacrylate; potassium carbomer; potassium carrageenan;potassium chloride; potassium palmate; potassium polyacrylate; potassiumsulfate; potato starch modified; PPG-2 cocamide; PPG-1 hydroxyethylcaprylamide; PPG-2 hydroxyethyl cocamide; PPG-2 hydroxyethylcoco/isostearamide; PPG-3 hydroxyethyl soyamide; PPG-14 laureth-60 hexyldicarbamate; PPG-14 laureth-60 isophoryl dicarbamate; PPG-14 palmeth-60hexyl dicarbamate; propylene glycol alginate; PVP/decene copolymer; PVPmontmorillonite; pyrus cydonia seed; pyrus malus (apple) fiber;rhizobian gum; ricebranamide DEA; ricinoleamide DEA; ricinoleamide MEA;ricinoleamide MIPA; ricinoleamidopropyl betaine; ricinoleic acid/adipicacid/AEEA copolymer; rosa multiflora flower wax; sclerotium gum;sesamide DEA; sesamidopropyl betaine; sodium acrylate/acryloyldimethyltaurate copolymer; sodium acrylates/acrolein copolymer; sodiumacrylates/acrylonitrogens copolymer; sodium acrylates copolymer; sodiumacrylates crosspolymer; sodium acrylate/sodium acrylamidomethylpropanesulfonate copolymer; sodium acrylates/vinyl isodecanoate crosspolymer;sodium acrylate/vinyl alcohol copolymer; sodium carbomer; sodiumcarboxymethyl chitin; sodium carboxymethyl dextran; sodium carboxymethylbeta-glucan; sodium carboxymethyl starch; sodium carrageenan; sodiumcellulose sulfate; sodium chloride; sodium cyclodextrin sulfate; sodiumhydroxypropyl starch phosphate; sodium isooctylene/MA copolymer; sodiummagnesium fluorosilicate; sodium oleate; sodium palmitate; sodium palmkernelate; sodium polyacrylate; sodium polyacrylate starch; sodiumpolyacryloyldimethyl taurate; sodium polygamma-glutamate; sodiumpolymethacrylate; sodium polystyrene sulfonate; sodium silicoaluminate;sodium starch octenylsuccinate; sodium stearate; sodium stearoxyPG-hydroxyethylcellulose sulfonate; sodium styrene/acrylates copolymer;sodium sulfate; sodium tallowate; sodium tauride acrylates/acrylicacid/acrylonitrogens copolymer; sodium tocopheryl phosphate; solanumtuberosum (potato) starch; soyamide DEA; soyamidopropyl betaine;starch/acrylates/acrylamide copolymer; starch hydroxypropyltrimoniumchloride; stearamide AMP; stearamide DEA; stearamide DEA-distearate;stearamide DIBA-stearate; stearamide MEA; stearamide MEA-stearate;stearamide MIPA; stearamidopropyl betaine; steareth-60 cetyl ether;steareth-100/PEG-136/HDI copolymer; stearyl alcohol; stearyl betaine;sterculia urens gum; synthetic fluorphlogopite; tallamide DEA; tallowalcohol; tallowamide DEA; tallowamide MEA; tallowamidopropyl betaine;tallowamidopropyl hydroxysultaine; tallowamine oxide; tallow betaine;tallow dihydroxyethyl betaine; tamarindus indica seed gum; tapiocastarch; TEA-alginate; TEA-carbomer; TEA-hydrochloride; trideceth-2carboxamide MEA; tridecyl alcohol; triethylene glycol dibenzoate;trimethyl pentanol hydroxyethyl ether; triticum vulgare (wheat) germpowder; triticum vulgare (wheat) kernel flour; triticum vulgare (wheat)starch; tromethamine acrylates/acrylonitrogens copolymer; tromethaminemagnesium aluminum silicate; undecyl alcohol; undecylenamide DEA;undecylenamide MEA; undecylenamidopropyl betaine; welan gum; wheatgermamide DEA; wheat germamidopropyl betaine; xanthan gum; yeastbeta-glucan; yeast polysaccharides and zea mays (corn) starch.

In some embodiments, one function of the carrier is to enhance skinpenetration of the active ingredients. Permeation enhancers arecompounds which promote skin permeability by altering the skin as abarrier to the flux of a desired penetrant. These may be classified assolvents, surfactants and miscellaneous chemicals. Suitable carriers arewell known to skilled practitioners, and include liposomes, ethanol,dimethylsulfoxide (DMSO), petroleum jelly (petrolatum), mineral oil(liquid petrolatum), water, deimethylformamide,dekaoxyethylene-oleylether, oleic acid, 2-pyrrolidone, Azone® brandpenetration enhancer (Upjohn), biologically acceptable glycols,diglycols, polyglycols; alkyoxy C2-C8 alcohols, ethoxydiglycol anddimethyl isosorbide. A skin penetration enhancer may be included atconcentrations ranging from 5% to 95%, preferably 5% to 10% of the totalcomposition.

In a further embodiment of the combinations described above, a topicalformulation is prepared that comprises a composition for cosmetic ordermatological use, which composition comprises a cosmetically and/ordermatologically effective amount of the combination stated above.

In one embodiment, the compositions are in a form suitable for cosmeticapplication including, but not limited to, lotions, ointments, creams,sprays, spritzes, aqueous or aqueous-alcoholic mixture gels, mousses,patches, pads, masks, moistened clothes, wipes, solid sticks, clearsticks, lip sticks, aerosol creams, anhydrous powders, talcs, tonics,oils, emulsions or bath salts.

In another embodiment, the composition also containsirritation-mitigating additives to minimize or eliminate the possibilityof skin irritation or skin damage resulting from the chemical compoundto be administered, or other components of the composition. Suitableirritation-mitigating additives include for example: tocopherols,monoamine oxidase inhibitors (e.g., 2-phenyl-1-ethanol), glycerin,salicylates, ascorbates (e.g., tetrahexyldecyl ascorbate), ionophores(e.g., monensin), amphiphilic amines, animonium chloride,N-acetylcysteine, capsaicin, and/or chloroquine.

Modulation of Melanin Production

In some embodiments, the compositions disclosed herein modulate melaninproduct in a subject in need thereof. For example, the compositionsdisclosed herein may decrease melanin production to reduce pigmentationin a subject in need thereof. The compositions disclosed herein may alsofunction to decrease the number of melanocytes present in the epidermis,effectively decreasing melanin production and reducing pigmentation in asubject in need thereof. A decrease in melanin production may bedesirable in the skin, hair, pigmented pigmented tissue underlying theiris of the eye, or the stria vascularis of the inner ear.Administration or targeting of the compositions disclosed herein may actto locally effect melanin production and reduce pigmentation.

Hyperpigmentation or hypermelanosis disorders due to environmentalstressors, such as hormonal imbalance, can also affect melanin orpigmentation levels in the skin. Hyperpigmentation or hypermelanosisdisorders may also be due to physiological stressors or mechanicalstressors.

Prostaglandin F2 alpha (PGF2 alpha) is a bioactive molecule in theprostanoid family of lipid mediators that regulate numerous processes inthe body, including inflammation. While not wishing to be limited to aspecific theory or mechanism of action, it is believed that thecompositions disclosed herein may act in two (2) ways to modulatemelanin distribution: 1) through the modulation of melanin production bymelanocytes; and 2) by affecting melanin distribution by melanocytes.

4-ethoxybenzaldehyde has been demonstrated to affect a wide variety ofinflammatory conditions, such as rheumatoid arthritis, febrileconditions, edema, hyperalgesia, inflammatory bowel disease, andperiodontal disease. However, 4-ethoxybenzaldehyde has not previouslybeen shown to be useful in the treatment of hyperpigmentation, includingpost-inflammatory hyperpigmentation, or to lighten skin.

In one aspect, provided herein is a method of treating hyperpigmentationor a hypermelanosis disorder in an individual, comprising administeringto the individual in need thereof an effective amount of a compositioncomprising: from about 0.01% to about 2% substituted benzaldehyde, about0.01% to about 5.0% each of Retinol, Niacinamide, TetrahexyldecylAscorbate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol,ethyl linoleate, and a pharmaceutically or cosmetically acceptablecarrier. In one embodiment, the amount of substituted benzaldehyde inthe composition is about 0.5%. In another embodiment, the compositioncomprises from about 0.1% to about 0.75%, from about 0.05% to about1.0%, or from about 0.01% to about 2% Retinol. In another embodiment,the composition comprises from about 2.0% to about 8.0%, from about 1%to about 10%, or from about 0.5% to about 15.0% Niacinamide. In anotherembodiment, the composition comprises from about 1.0% to about 5.0%,from about 0.5% to about 8.0%, or from about 0.1% to about 15%Tetrahexyldecyl Ascorbate. In another embodiment, the compositioncomprises from about 0.001% to about 0.5%, from about 0.0005% to about1.0% or from about 0.0001% to about 2% Licorice root extract. In anotherembodiment, the composition comprises from about 0.1% to about 3.0%,from about 0.05% to about 5.0%, or from about 0.01% to about 10.0%Resorcinol. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In another aspect, provided herein is a method of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: about 0.1% to about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In another aspect, provided herein is a method of treatinghyperpigmentation or a hypermelanosis disorder in an individual,comprising administering to the individual in need thereof an effectiveamount of a composition comprising: about 0.5% 4-ethoxybenzaldehyde,about 0.01% to about 5.0% each of Retinol, Niacinamide, TetrahexyldecylAscorbate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol,ethyl linoleate, and a pharmaceutically or cosmetically acceptablecarrier. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

In some embodiments, the method reduces melanin distribution by about10% to about 40%.

Application of the compositions in the methods described herein may betopical or transdermal administeration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

In one embodiment, hyperpigmentation may result from an environmentalstressor (e.g., excessive sun exposure or chemical exposure),physiological stressor (e.g., a hormonal disorder), or mechanicalstressor.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipients, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol,Dunaliella Salina Extract or combinations thereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

In another aspect, provided herein is a method of lightening skin in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising: from about 0.01% toabout 2% substituted benzaldehyde, about 0.01% to about 5.0% each ofRetinol, Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra(Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In one embodiment,the amount of substituted benzaldehyde in the composition is about 0.5%.In another embodiment, the composition comprises from about 0.1% toabout 0.75%, from about 0.05% to about 1.0%, or from about 0.01% toabout 2% Retinol. In another embodiment, the composition comprises fromabout 2.0% to about 8.0%, from about 1% to about 10%, or from about 0.5%to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In another aspect, provided herein is a method of lightening skin in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising: about 0.1% to about0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the amount ofsubstituted benzaldehyde in the composition is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In another aspect, provided herein is a method of lightening skin in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising: about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In one embodiment, the amount ofsubstituted benzaldehyde in the composition is about 0.5%. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol.

In another embodiment, the composition comprises from about 0.1% toabout 3.0%, from about 0.05% to about 5.0%, or from about 0.01% to about10.0% ethyl linoleate.

In some embodiments, the methods decrease the level of pigmentation byabout 5%, by about 10%, by about 20%, by about 30% or by about 40%.

The methods may be used to treat hyperpigmentation or a hypermelanosisdisorder. In one embodiment, hyperpigmentation may result from anenvironmental stressor (e.g., excessive sun exposure or chemicalexposure), physiological stressor (e.g., a hormonal disorder), ormechanical stressor.

In some embodiments, the method reduces melanin distribution by about10% to about 40%.

Application of the compositions in the methods described herein may betopical or transdermal administeration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipients, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, tetrahexyldecylTocopherol, Dunaliella Salina Extract or combinations thereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phyticacid or combinations thereof.

Provided are methods of modifying melanin distribution by modulatingprostaglandin F2 alpha (PGF2 alpha) in a cell, comprising contactingsaid cell with a composition comprising from about 0.01% to about 2%substituted benzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In some embodiments, the cells beingtreated are located in skin of an individual.

Also disclosed are methods of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in skin cells in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising from about 0.01% toabout 2% substituted benzaldehyde, about 0.01% to about 5.0% each ofRetinol, Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra(Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In anotherembodiment, the composition comprises from about 0.1% to about 0.75%,from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol.In another embodiment, the composition comprises from about 2.0% toabout 8.0%, from about 1% to about 10%, or from about 0.5% to about15.0% Niacinamide. In another embodiment, the composition comprises fromabout 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate.

In one embodiment, the amount of substituted benzaldehyde in thecomposition is about 0.5%.

Substituted benzaldehydes for use in the compositions include, forexample, 2-ethoxybenzaldehyde, 4-ethoxybenzaldehyde,4-allyloxybenzaldehyde or 4-propoxybenzaldehyde. In one embodiment, thesubstituted benzaldehyde is 4-ethoxybenzaldehyde, which may be presentin the composition in an amount of about 0.5%.

In some embodiments, provided are methods of modifying melanindistribution by modulating prostaglandin F2 alpha (PGF2 alpha) in acell, comprising contacting said cell with a composition comprisingabout 0.1 to about 0.5% 4-ethoxybenzaldehyde, about 0.01% to about 5.0%each of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate, GlycyrrhizaGlabra (Licorice) Root Extract, Hexyl Resorcinol, ethyl linoleate, and apharmaceutically or cosmetically acceptable carrier. In someembodiments, the cells being treated are located in skin of anindividual. In another embodiment, the composition comprises from about0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01%to about 2% Retinol. In another embodiment, the composition comprisesfrom about 2.0% to about 8.0%, from about 1% to about 10%, or from about0.5% to about 15.0% Niacinamide. In another embodiment, the compositioncomprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%,or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In anotherembodiment, the composition comprises from about 0.001% to about 0.5%,from about 0.0005% to about 1.0% or from about 0.0001% to about 2%Licorice root extract. In another embodiment, the composition comprisesfrom about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or fromabout 0.01% to about 10.0% Resorcinol. In another embodiment, thecomposition comprises from about 0.1% to about 3.0%, from about 0.05% toabout 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Provided are methods of modifying melanin distribution by modulatingprostaglandin F2 alpha (PGF2 alpha) in a cell, comprising contactingsaid cell with a composition comprising about 0.5% 4-ethoxybenzaldehyde,about 0.01% to about 5.0% each of Retinol, Niacinamide, TetrahexyldecylAscorbate, Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol,ethyl linoleate, and a pharmaceutically or cosmetically acceptablecarrier. In some embodiments, the cells being treated are located inskin of an individual. In another embodiment, the composition comprisesfrom about 0.1% to about 0.75%, from about 0.05% to about 1.0%, or fromabout 0.01% to about 2% Retinol. In another embodiment, the compositioncomprises from about 2.0% to about 8.0%, from about 1% to about 10%, orfrom about 0.5% to about 15.0% Niacinamide. In another embodiment, thecomposition comprises from about 1.0% to about 5.0%, from about 0.5% toabout 8.0%, or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate.In another embodiment, the composition comprises from about 0.001% toabout 0.5%, from about 0.0005% to about 1.0% or from about 0.0001% toabout 2% Licorice root extract. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% Resorcinol. In another embodiment,the composition comprises from about 0.1% to about 3.0%, from about0.05% to about 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

Also provided are methods of modifying melanin distribution bymodulating prostaglandin F2 alpha (PGF2 alpha) in skin cells in anindividual, comprising administering to the individual in need thereofan effective amount of a composition comprising about 0.5%4-ethoxybenzaldehyde, about 0.01% to about 5.0% each of Retinol,Niacinamide, Tetrahexyldecyl Ascorbate, Glycyrrhiza Glabra (Licorice)Root Extract, Hexyl Resorcinol, ethyl linoleate, and a pharmaceuticallyor cosmetically acceptable carrier. In another embodiment, thecomposition comprises from about 0.1% to about 0.75%, from about 0.05%to about 1.0%, or from about 0.01% to about 2% Retinol. In anotherembodiment, the composition comprises from about 2.0% to about 8.0%,from about 1% to about 10%, or from about 0.5% to about 15.0%Niacinamide. In another embodiment, the composition comprises from about1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% toabout 15% Tetrahexyldecyl Ascorbate. In another embodiment, thecomposition comprises from about 0.001% to about 0.5%, from about0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice rootextract. In another embodiment, the composition comprises from about0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01%to about 10.0% Resorcinol. In another embodiment, the compositioncomprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%,or from about 0.01% to about 10.0% ethyl linoleate. In some embodiments,the method reduces melanin distribution by about 10% to about 40%.

Application of the compositions in the methods described herein may betopical or transdermal administeration to the skin of the individual.

In one embodiment, the pharmaceutically or cosmetically acceptablecarrier is a topical carrier. Topical carriers include, for example, awater-in-oil emulsion, cream, liquid, gel, oil, paste, ointment,suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-wateremulsion, water-in-silicone emulsion, spray or serum carrier.

Compositions described herein for use in such methods may furtherinclude one or more additional active agents. For example, an additionalactive agent may be an antioxidant, a sunscreen, a sunprotectant, asunblock, a skin-lightening agent, an anti-inflammatory agent, ananti-acne agent or mixtures thereof. Compositions described herein foruse in such methods may further include one or more of a solvent, filmformer, preservative, viscosity increasing agent, fragrance, surfactant,chelating agent, humectant, permeation enhancer, excipients, or acombination thereof.

Exemplary antioxidants include vitamin E, Coenzyme Q10, idebenone,lycopene, green tea polyphenols, silybin, resveratrol, grape seedextract, Oregon grape root (Mahonia aquifolium) extract, pomegranateextract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol,Dunaliella Salina Extract or combinations thereof.

Exemplary skin-lightening agents include hydroquinone, monobenzyl etherof hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soyproteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid,hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin,4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol,N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexamincacid, an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), orphytic acid combinations thereof.

In one aspect, one patient population to be treated by the presentmethods is described below in Example 13. Representative patientsinclude those with Fitzpatrick skin types I-IV. Fitzpatrick skinclassification is based on the skin's unprotected response to the first30 to 45 minutes of sun exposure after a winter season without sunexposure. The categories of skin types are as follows: (I): Always burnseasily; never tans; (II): Always burns easily; tans minimally; (III):Burns moderately; tans gradually; (IV): Burns minimally; always tanswell; (V): Rarely burns; tans profusely; and (VI): Never burns; deeplypigmented. Patients also may exhibit the presence of clinicallydetermined moderate to severe dyspigmentation on the face as determinedby a score of 4-9 from the Overall Hyperpigmentation scale. Individualsto be treated are in good general health and free of any disease stateor physical condition (e.g., psoriasis, moderate to severe rosacea,hirsutism, scars, tattoos, etc.) which might increase the health risk tothe subject by treatment. Individuals to be treated include those whohave not used systemic retinoids (e.g., Tazorac, Soriataine, Accutane,etc.) and/or any other systemic medication known to affect melasma atleast 60 days prior to treatment and are not to use these productsduring treatment. Individuals to be treated are not to use topicalretinoids and/or all other topical medication (e.g., topical steroids,products containing benzoyl peroxide, alpha- or beta-hydroxy acids,hydroquinone, and/or any other over the counter (OTC) skin treatmentmedications) to the facial area known to affect melasma at least 14 daysprior to treatment and are not to use these products during treatment.Patients should be willing to avoid extended periods of sun exposureduring treatment. If brief (less than 20 minutes) periods of sunexposure cannot be avoided, then subjects are asked to use an SPF 30product and wear protective clothing prior to and during exposure.

In another aspect, an individual will not be eligible for treatment ifthey meet any of the following exclusion criteria: Individuals withknown allergies or sensitivities to skin lightening products, retinoids,hydroquinone, sulfites, moisturizers, or other facial products.Individuals with active symptoms of allergy, active psoriasis or eczema,sunburn, excessive scarring, tattoos, or other skin condition in theareas to be treated. Individuals who are nursing, pregnant, or planningto become pregnant during treatment. Individuals having uncontrolleddisease such as diabetes, hypertension, hyper or hypo-thyroidism, activehepatitis, immune deficiency, or autoimmune disease as determined by theinitial paperwork. Individuals who require electrolysis, waxing, or usedepilatories on the face during conduct of the study. Individuals whohave had a facial peel or a laser treatment of the face within 60 daysprior to treatment. Individuals who have a pre-existing or dormantdermatologic condition (e.g., psoriasis, atopic dermatitis, advancedskin cancer, rosacea, other inflammatory disorder, etc.). Individualswho are receiving treatment for a skin disorder with anothercomposition.

In another aspect, another patient population to be treated by thepresent methods is described below in Example 14. Representativepatients include those with Fitzpatrick skin type III and those who arein general good health as determined by review of their health.

In another aspect, an individual will not be eligible for treatment ifthey meet any of the following exclusion criteria: Individuals withFitzpatrick skin types I, II, IV, V and VI. Individuals that have beeninstructed by a physician, pharmacist, or health professional to avoidsunlight because of a medical condition and/or because of drugcontraindications. Individuals with known abnormal responses to sunlightor UVR light sources. Individuals with a known allergy to any ingredientin a personal care product. Individuals with known atopic skin diseasesor neurodermatitis. Women known to be pregnant, nursing, or planning tobecome pregnant within 6 months. Individuals known to be treated forcancer or have a history of cancer. Individuals with observable sunburn,suntan, scars, uneven tone/pigmentation, nevi or other dermal conditionson the areas to be treated that might influence the results. Individualswith uncontrolled high blood pressure, individuals with dermalhypersensitivity requiring treatments with medications. Individualstaking medication(s) which would interfere with the subject's treatment.Such medications include, but are not limited to, antihypertensiveagents (hydrochorothiazide, furosemide, meticrane), ataractics (e.g.,perphenazine), psychotropic agents (e.g., chlorpromazine),antihistamines (e.g., promethazine hydrochloride), oral hypoglycemicagents (e.g., tolubutamide, chlorpropamide), and tetracyclineantibiotics (e.g., dimethylchlorotetracycline, tetracycline).

Method of Administration

In some embodiments, any composition described herein is administered inthe form of a cosmetic composition. In some embodiments, the cosmeticcomposition can be prepared according to procedures well known in thecosmetic arts and comprise at least one active compound and twoantioxidant agents.

In some embodiments, the cosmetic composition is administered topically.In specific embodiments, the cosmetic composition is administeredtransdermally so that the active agent and antioxidant agents contactthe skin. In a further or additional embodiment, the composition isadministered transdermally so as to deliver the compositions disclosedherein systemically.

The compositions disclosed herein contain one or more substitutedbenzaldehyde and an optional at least one additional active agent. Theamounts used are amounts effective such that when administered to asubject for treating a disease, cosmetic or dermatological condition, issufficient to effect such treatment for the disease, cosmetic ordermatological condition. Here, the amount will depend upon the endpointdesired, for example, the modification, for example the increase orreduction of melanin and/or melanocyte production and/or distribution.The endpoint can be measured in terms of the subjective interpretationof the subject being administered the disclosed compositions. Forexample, the endpoint may be a study by which a subject is queried ifthe treatment regimen is “satisfactory” or “unsatisfactory”.Alternatively, the endpoint may be measured quantitatively in terms ofthe amount of melanin and/or melanocytes in a given subject orexperimental procedure. The endpoint may be measured by a trainedmedical professional, for example a physician or nurse, or by a subjector other individual. The endpoint may additionally be determinedremotely, for example, through comparisons of photographs or otherrecordings by a trained medical professional or other individual.Furthermore, the degree of modification of melanin production may bepredetermined by a trained medical professional, for example, byassigning a predetermined degree of melanin and/or melanocyte presenceas an endpoint value.

The “effective amount”, however, will take into account any toxicityeffects that may occur, for example, severe skin irritation with higherdoses of the active agents disclosed herein. Suggested endpoints mayfirst be measured in vitro or in an animal model to determine theacceptable range of active agents to be used in conjunction with thecompositions disclosed herein. One of ordinary skill in the art can thenextrapolate doses that will avoid toxicity but maintain efficacy intreated subjects, including humans. The “effective amount” can varydepending on the compound, the disease and its severity, and the age,weight, etc., of the subject to be treated.

In certain embodiments, the compositions disclosed herein comprises asubstituted benzaldehyde in a concentration of about 0.01%, about 0.05%,about 0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about0.8%, about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about2.3%, about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%,about 8%, about 10%, about 13%, about 15%, about 18%, about 20%, about22% or about 25%. Preferably, the compositions disclosed hereincomprises a substituted benzaldehyde in a concentration from about 0.01%to about 50%, from about 0.1% to about 30%, from about 0.1% to about20%, from about 0.5% to about 20%, from about 0.5% to about 10%, fromabout 0.5% to about 5%, from about 0.5% to about 3%, from about 0.5% toabout 2.0%, from about 0.5% to about 1.5%, from about 0.75% to about10%, from about 0.75% to about 7.5%, from about 0.75% to about 5%, fromabout 1% to about 10%, from about 1% to about 5%, from about 1% to about2.5%, from about 1% to about 2%, from about 0.1% to about 2%, from about0.01% to about 2%, from about 0.01% to about 2%, from about 0.01% toabout 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, orfrom about 0.5% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of substituted benzaldehyde or about 0.1 mg to about 10 mgof substituted benzaldehyde. In some embodiments, the compositionsdisclosed herein may contain from about 0.05 to about 5 mg ofsubstituted benzaldehyde, or from about 0.1 to about 3 mg of substitutedbenzaldehyde. In some embodiments, the compositions disclosed herein maycontain from about 0.1 to about 50 mg, from about 0.1 to about 45 mg,from about 0.1 to about 40 mg, from about 0.1 to about 35 mg, from about0.1 to about 30 mg, from about 0.1 to about 25 mg, from about 0.1 toabout 20 mg, from about 0.1 to about 15 mg, from about 0.1 to about 10mg, from about 0.1 to about 5 mg, from about 0.5 to about 50 mg, fromabout 0.5 to about 45 mg, from about 0.5 to about 40 mg, from about 0.5to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 to about25 mg, from about 0.5 to about 20 mg, from about 0.5 to about 15 mg,from about 0.5 to about 10 mg, from about 0.5 to about 5 mg, from about1.0 to about 50 mg, from about 1.0 to about 45 mg, from about 1.0 toabout 40 mg, from about 1.0 to about 35 mg, from about 1.0 to about 30mg, from about 1.0 to about 25 mg, from about 1.0 to about 20 mg, fromabout 1.0 to about 15 mg, from about 1.0 to about 10 mg, from about 1.0to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 to about 45mg, from about 2.5 to about 40 mg, from about 2.5 to about 35 mg, fromabout 2.5 to about 30 mg, from about 2.5 to about 25 mg, from about 2.5to about 20 mg, from about 2.5 to about 15 mg, from about 2.5 to about10 mg, and from about 2.5 to about 5 mg of substituted benzaldehyde. Insome embodiments, the compositions disclosed herein will contain fromabout 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg,0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80mg, 90 mg or 100 mg of substituted benzaldehyde. In some embodiments,the compositions disclosed herein will contain from about 0.3 mg toabout 0.75 mg of substituted benzaldehyde.

In some embodiment, the compositions disclosed herein comprises4-ethoxybenzaldehyde in a concentration of about 0.01%, about 0.05%,about 0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about0.8%, about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about2.3%, about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%,about 8%, about 10%, about 13%, about 15%, about 18%, about 20%, about22%, about 25%, about 30% or about 40%. Preferably, the compositionsdisclosed herein comprises a 4-ethoxybenzaldehyde in a concentrationfrom about 0.01% to about 50%, from about 0.1% to about 30%, from about0.1% to about 20%, from about 0.5% to about 20%, from about 0.5% toabout 10%, from about 0.5% to about 5%, from about 0.5% to about 3%,from about 0.5% to about 2.0%, from about 0.5% to about 1.5%, from about0.75% to about 10%, from about 0.75% to about 7.5%, from about 0.75% toabout 5%, from about 1% to about 10%, from about 1% to about 5%, fromabout 1% to about 2.5%, from about 1% to about 2%, from about 0.1% toabout 2%, from about 0.01% to about 2%, from about 0.01% to about 2%,from about 0.01% to about 2%, from about 0.1% to about 1%, from about0.1% to about 0.5%, or from about 0.5% to about 2%.

The compositions disclosed herein may also have a concentration of4-ethoxybenzaldehyde of from about 0.01 mg/ml to about 50 mg/ml,preferably from about 0.1 mg/ml to about 10 mg/ml. In some embodiments,the compositions disclosed herein may have a concentration of4-ethoxybenzadehyde of from about 0.1 mg/ml to about 5 mg/ml, or fromabout 0.3 mg/ml to about 3 mg/ml. In some embodiments, the compositionswill have a concentration of 4-ethoxybenzaldehyde of from about 0.1 toabout 50 mg/ml, from about 0.1 to about 45 mg/ml, from about 0.1 toabout 40 mg/ml, from about 0.1 to about 35 mg/ml, from about 0.1 toabout 30 mg/ml, from about 0.1 to about 25 mg/ml, from about 0.1 toabout 20 mg/ml, from about 0.1 to about 15 mg/ml, from about 0.1 toabout 10 mg/ml, from about 0.1 to about 5 mg/ml, 0.5 to about 50 mg/ml,from about 0.5 to about 45 mg/ml, from about 0.5 to about 40 mg/ml, fromabout 0.5 to about 35 mg/ml, from about 0.5 to about 30 mg/ml, fromabout 0.5 to about 25 mg/ml, from about 0.5 to about 20 mg/ml, fromabout 0.5 to about 15 mg/ml, from about 0.5 to about 10 mg/ml, fromabout 0.5 to about 5 mg/ml, 1.0 to about 50 mg/ml, from about 1.0 toabout 45 mg/ml, from about 1.0 to about 40 mg/ml, from about 1.0 toabout 35 mg/ml, from about 1.0 to about 30 mg/ml, from about 1.0 toabout 25 mg/ml, from about 1.0 to about 20 mg/ml, from about 1.0 toabout 15 mg/ml, from about 1.0 to about 10 mg/ml, from about 1.0 toabout 5 mg/ml, 2.5 to about 50 mg/ml, from about 2.5 to about 45 mg/ml,from about 2.5 to about 40 mg/ml, from about 2.5 to about 35 mg/ml, fromabout 2.5 to about 30 mg/ml, from about 2.5 to about 25 mg/ml, fromabout 2.5 to about 20 mg/ml, from about 2.5 to about 15 mg/ml, fromabout 2.5 to about 10 mg/ml, from about 2.5 to about 5 mg/ml of4-ethoxybenzaldehyde. In some embodiments, the compositions disclosedherein will have a concentration of 4-ethoxybenzaldehyde of 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11,11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 25, 30, 3540, 45 or 50 mg/ml.

In other embodiments, the compositions disclosed herein further includesan antioxidant in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of antioxidant from about 0.1% to about 25%, fromabout 0.5% to about 20%, from about 0.5% to about 10%, from about 0.5%to about 5%, from about 0.5% to about 3%, from about 0.75% to about 10%,from about 0.75% to about 7.5%, from about 0.75% to about 5%, from about1% to about 10%, from about 1% to about 5%, from about 1% to about 2.5%,or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of antioxidant or about 0.1 mg to about 10 mg ofantioxidant. In some embodiments, the compositions disclosed herein maycontain from about 0.05 to about 5 mg of antioxidant, or from about 0.1to about 3 mg of antioxidant. In some embodiments, the compositionsdisclosed herein may contain from about 0.1 to about 50 mg, from about0.1 to about 45 mg, from about 0.1 to about 40 mg, from about 0.1 toabout 35 mg, from about 0.1 to about 30 mg, from about 0.1 to about 25mg, from about 0.1 to about 20 mg, from about 0.1 to about 15 mg, fromabout 0.1 to about 10 mg, from about 0.1 to about 5 mg, from about 0.5to about 50 mg, from about 0.5 to about 45 mg, from about 0.5 to about40 mg, from about 0.5 to about 35 mg, from about 0.5 to about 30 mg,from about 0.5 to about 25 mg, from about 0.5 to about 20 mg, from about0.5 to about 15 mg, from about 0.5 to about 10 mg, from about 0.5 toabout 5 mg, from about 1.0 to about 50 mg, from about 1.0 to about 45mg, from about 1.0 to about 40 mg, from about 1.0 to about 35 mg, fromabout 1.0 to about 30 mg, from about 1.0 to about 25 mg, from about 1.0to about 20 mg, from about 1.0 to about 15 mg, from about 1.0 to about10 mg, from about 1.0 to about 5 mg, from about 2.5 to about 50 mg, fromabout 2.5 to about 45 mg, from about 2.5 to about 40 mg, from about 2.5to about 35 mg, from about 2.5 to about 30 mg, from about 2.5 to about25 mg, from about 2.5 to about 20 mg, from about 2.5 to about 15 mg,from about 2.5 to about 10 mg, and from about 2.5 to about 5 mg ofantioxidant. In some embodiments, the compositions disclosed herein willcontain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70mg, 80 mg, 90 mg or 100 mg of antioxidant. In some embodiments, thecompositions disclosed herein will contain from about 0.3 mg to about0.75 mg of antioxidant.

In other embodiments, the compositions disclosed herein furthercomprises a skin-lightening agent in a concentration of about 0.01%,about 0.05%, about 0.08%, about 0.1%, about 0.15%, about 0.2%, about0.5%, about 0.8%, about 1%, about 1.3%, about 1.5%, about 1.8%, about2%, about 2.3%, about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%,about 5%, about 8%, about 10%, about 13%, about 15%, about 18%, about20%, about 23%, about 25%. In yet other embodiments, the compositionsdisclosed herein comprises a range of skin-lightening agents from about0.1% to about 25%, from about 0.5% to about 20%, from about 0.5% toabout 10%, from about 0.5% to about 5%, from about 0.5% to about 3%,from about 0.75% to about 10%, from about 0.75% to about 7.5%, fromabout 0.75% to about 5%, from about 1% to about 10%, from about 1% toabout 5%, from about 1% to about 2.5%, or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of skin-lightening agent or about 0.1 mg to about 10 mg ofskin-lightening agent. In some embodiments, the compositions disclosedherein may contain from about 0.05 to about 5 mg of skin-lighteningagent, or from about 0.1 to about 3 mg of skin-lightening agent. In someembodiments, the compositions disclosed herein may contain from about0.1 to about 50 mg, from about 0.1 to about 45 mg, from about 0.1 toabout 40 mg, from about 0.1 to about 35 mg, from about 0.1 to about 30mg, from about 0.1 to about 25 mg, from about 0.1 to about 20 mg, fromabout 0.1 to about 15 mg, from about 0.1 to about 10 mg, from about 0.1to about 5 mg, from about 0.5 to about 50 mg, from about 0.5 to about 45mg, from about 0.5 to about 40 mg, from about 0.5 to about 35 mg, fromabout 0.5 to about 30 mg, from about 0.5 to about 25 mg, from about 0.5to about 20 mg, from about 0.5 to about 15 mg, from about 0.5 to about10 mg, from about 0.5 to about 5 mg, from about 1.0 to about 50 mg, fromabout 1.0 to about 45 mg, from about 1.0 to about 40 mg, from about 1.0to about 35 mg, from about 1.0 to about 30 mg, from about 1.0 to about25 mg, from about 1.0 to about 20 mg, from about 1.0 to about 15 mg,from about 1.0 to about 10 mg, from about 1.0 to about 5 mg, from about2.5 to about 50 mg, from about 2.5 to about 45 mg, from about 2.5 toabout 40 mg, from about 2.5 to about 35 mg, from about 2.5 to about 30mg, from about 2.5 to about 25 mg, from about 2.5 to about 20 mg, fromabout 2.5 to about 15 mg, from about 2.5 to about 10 mg, and from about2.5 to about 5 mg of skin-lightening agent. In some embodiments, thecompositions disclosed herein will contain from about 0.1 mg, 0.2 mg,0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg,3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg,35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg ofskin-lightening agent. In some embodiments, the compositions disclosedherein will contain from about 0.3 mg to about 0.75 mg ofskin-lightening agent.

In some embodiments, the compositions disclosed herein further comprisesa sunscreen agent in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of sunscreen agents from about 0.1% to about 25%, fromabout 0.5% to about 20%, from about 0.5% to about 10%, from about 0.5%to about 5%, from about 0.5% to about 3%, from about 0.75% to about 10%,from about 0.75% to about 7.5%, from about 0.75% to about 5%, from about1% to about 10%, from about 1% to about 5%, from about 1% to about 2.5%,or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of a sunscreen agent or about 0.1 mg to about 10 mg of asunscreen agent. In some embodiments, the compositions disclosed hereinmay contain from about 0.05 to about 5 mg of sunscreen agent, or fromabout 0.1 to about 3 mg of sunscreen agent. In some embodiments, thecompositions disclosed herein may contain from about 0.1 to about 50 mg,from about 0.1 to about 45 mg, from about 0.1 to about 40 mg, from about0.1 to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 toabout 25 mg, from about 0.1 to about 20 mg, from about 0.1 to about 15mg, from about 0.1 to about 10 mg, from about 0.1 to about 5 mg, fromabout 0.5 to about 50 mg, from about 0.5 to about 45 mg, from about 0.5to about 40 mg, from about 0.5 to about 35 mg, from about 0.5 to about30 mg, from about 0.5 to about 25 mg, from about 0.5 to about 20 mg,from about 0.5 to about 15 mg, from about 0.5 to about 10 mg, from about0.5 to about 5 mg, from about 1.0 to about 50 mg, from about 1.0 toabout 45 mg, from about 1.0 to about 40 mg, from about 1.0 to about 35mg, from about 1.0 to about 30 mg, from about 1.0 to about 25 mg, fromabout 1.0 to about 20 mg, from about 1.0 to about 15 mg, from about 1.0to about 10 mg, from about 1.0 to about 5 mg, from about 2.5 to about 50mg, from about 2.5 to about 45 mg, from about 2.5 to about 40 mg, fromabout 2.5 to about 35 mg, from about 2.5 to about 30 mg, from about 2.5to about 25 mg, from about 2.5 to about 20 mg, from about 2.5 to about15 mg, from about 2.5 to about 10 mg, and from about 2.5 to about 5 mgof sunscreen agent. In some embodiments, the compositions disclosedherein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg,0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg,7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg of sunscreen agent. In someembodiments, the compositions disclosed herein will contain from about0.3 mg to about 0.75 mg of sunscreen agent.

In some embodiments, the compositions disclosed herein further comprisesan anti-acne agent in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of an anti-acne agent from about 0.1% to about 25%,from about 0.5% to about 20%, from about 0.5% to about 10%, from about0.5% to about 5%, from about 0.5% to about 3%, from about 0.75% to about10%, from about 0.75% to about 7.5%, from about 0.75% to about 5%, fromabout 1% to about 10%, from about 1% to about 5%, from about 1% to about2.5%, or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of anti-acne agent or about 0.1 mg to about 10 mg ofanti-acne agent. In some embodiments, the compositions disclosed hereinmay contain from about 0.05 to about 5 mg of anti-acne agent, or fromabout 0.1 to about 3 mg of anti-acne agent. In some embodiments, thecompositions disclosed herein may contain from about 0.1 to about 50 mg,from about 0.1 to about 45 mg, from about 0.1 to about 40 mg, from about0.1 to about 35 mg, from about 0.1 to about 30 mg, from about 0.1 toabout 25 mg, from about 0.1 to about 20 mg, from about 0.1 to about 15mg, from about 0.1 to about 10 mg, from about 0.1 to about 5 mg, fromabout 0.5 to about 50 mg, from about 0.5 to about 45 mg, from about 0.5to about 40 mg, from about 0.5 to about 35 mg, from about 0.5 to about30 mg, from about 0.5 to about 25 mg, from about 0.5 to about 20 mg,from about 0.5 to about 15 mg, from about 0.5 to about 10 mg, from about0.5 to about 5 mg, from about 1.0 to about 50 mg, from about 1.0 toabout 45 mg, from about 1.0 to about 40 mg, from about 1.0 to about 35mg, from about 1.0 to about 30 mg, from about 1.0 to about 25 mg, fromabout 1.0 to about 20 mg, from about 1.0 to about 15 mg, from about 1.0to about 10 mg, from about 1.0 to about 5 mg, from about 2.5 to about 50mg, from about 2.5 to about 45 mg, from about 2.5 to about 40 mg, fromabout 2.5 to about 35 mg, from about 2.5 to about 30 mg, from about 2.5to about 25 mg, from about 2.5 to about 20 mg, from about 2.5 to about15 mg, from about 2.5 to about 10 mg, and from about 2.5 to about 5 mgof anti-acne agent. In some embodiments, the compositions disclosedherein will contain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg,0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg,7.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg of anti-acne agent. In someembodiments, the compositions disclosed herein will contain from about0.3 mg to about 0.75 mg of anti-acne agent.

In some embodiments, the compositions disclosed herein further comprisesan anti-inflammatory agent in a concentration of about 0.01%, about0.05%, about 0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%,about 0.8%, about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%,about 2.3%, about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%,about 5%, about 8%, about 10%, about 13%, about 15%, about 18%, about20%, about 23%, about 25%. In yet other embodiments, the compositionsdisclosed herein comprises a range of anti-inflammatory agents fromabout 0.1% to about 25%, from about 0.5% to about 20%, from about 0.5%to about 10%, from about 0.5% to about 5%, from about 0.5% to about 3%,from about 0.75% to about 10%, from about 0.75% to about 7.5%, fromabout 0.75% to about 5%, from about 1% to about 10%, from about 1% toabout 5%, from about 1% to about 2.5%, or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of anti-inflammatory agent or about 0.1 mg to about 10 mgof anti-inflammatory agent. In some embodiments, the compositionsdisclosed herein may contain from about 0.05 to about 5 mg ofanti-inflammatory agent, or from about 0.1 to about 3 mg ofanti-inflammatory agent. In some embodiments, the compositions disclosedherein may contain from about 0.1 to about 50 mg, from about 0.1 toabout 45 mg, from about 0.1 to about 40 mg, from about 0.1 to about 35mg, from about 0.1 to about 30 mg, from about 0.1 to about 25 mg, fromabout 0.1 to about 20 mg, from about 0.1 to about 15 mg, from about 0.1to about 10 mg, from about 0.1 to about 5 mg, from about 0.5 to about 50mg, from about 0.5 to about 45 mg, from about 0.5 to about 40 mg, fromabout 0.5 to about 35 mg, from about 0.5 to about 30 mg, from about 0.5to about 25 mg, from about 0.5 to about 20 mg, from about 0.5 to about15 mg, from about 0.5 to about 10 mg, from about 0.5 to about 5 mg, fromabout 1.0 to about 50 mg, from about 1.0 to about 45 mg, from about 1.0to about 40 mg, from about 1.0 to about 35 mg, from about 1.0 to about30 mg, from about 1.0 to about 25 mg, from about 1.0 to about 20 mg,from about 1.0 to about 15 mg, from about 1.0 to about 10 mg, from about1.0 to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 toabout 45 mg, from about 2.5 to about 40 mg, from about 2.5 to about 35mg, from about 2.5 to about 30 mg, from about 2.5 to about 25 mg, fromabout 2.5 to about 20 mg, from about 2.5 to about 15 mg, from about 2.5to about 10 mg, and from about 2.5 to about 5 mg of anti-inflammatoryagent. In some embodiments, the compositions disclosed herein willcontain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70mg, 80 mg, 90 mg or 100 mg of anti-inflammatory agent. In someembodiments, the compositions disclosed herein will contain from about0.3 mg to about 0.75 mg of anti-inflammatory agent.

In some embodiments, the compositions disclosed herein further comprisesan emollient in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of emollients from about 0.1% to about 25%, from about0.5% to about 20%, from about 0.5% to about 10%, from about 0.5% toabout 5%, from about 0.5% to about 3%, from about 0.75% to about 10%,from about 0.75% to about 7.5%, from about 0.75% to about 5%, from about1% to about 10%, from about 1% to about 5%, from about 1% to about 2.5%,or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of emollient or about 0.1 mg to about 10 mg of emollient.In some embodiments, the compositions disclosed herein may contain fromabout 0.05 to about 5 mg of emollient, or from about 0.1 to about 3 mgof emollient. In some embodiments, the compositions disclosed herein maycontain from about 0.1 to about 50 mg, from about 0.1 to about 45 mg,from about 0.1 to about 40 mg, from about 0.1 to about 35 mg, from about0.1 to about 30 mg, from about 0.1 to about 25 mg, from about 0.1 toabout 20 mg, from about 0.1 to about 15 mg, from about 0.1 to about 10mg, from about 0.1 to about 5 mg, from about 0.5 to about 50 mg, fromabout 0.5 to about 45 mg, from about 0.5 to about 40 mg, from about 0.5to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 to about25 mg, from about 0.5 to about 20 mg, from about 0.5 to about 15 mg,from about 0.5 to about 10 mg, from about 0.5 to about 5 mg, from about1.0 to about 50 mg, from about 1.0 to about 45 mg, from about 1.0 toabout 40 mg, from about 1.0 to about 35 mg, from about 1.0 to about 30mg, from about 1.0 to about 25 mg, from about 1.0 to about 20 mg, fromabout 1.0 to about 15 mg, from about 1.0 to about 10 mg, from about 1.0to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 to about 45mg, from about 2.5 to about 40 mg, from about 2.5 to about 35 mg, fromabout 2.5 to about 30 mg, from about 2.5 to about 25 mg, from about 2.5to about 20 mg, from about 2.5 to about 15 mg, from about 2.5 to about10 mg, and from about 2.5 to about 5 mg of emollient. In someembodiments, the compositions disclosed herein will contain from about0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg,25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or100 mg of emollient. In some embodiments, the compositions disclosedherein will contain from about 0.3 mg to about 0.75 mg of emollient.

In some embodiments, the compositions disclosed herein further comprisesa film former in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of film formers from about 0.1% to about 25%, fromabout 0.5% to about 20%, from about 0.5% to about 10%, from about 0.5%to about 5%, from about 0.5% to about 3%, from about 0.75% to about 10%,from about 0.75% to about 7.5%, from about 0.75% to about 5%, from about1% to about 10%, from about 1% to about 5%, from about 1% to about 2.5%,or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of film former or about 0.1 mg to about 10 mg of filmformer. In some embodiments, the compositions disclosed herein maycontain from about 0.05 to about 5 mg of emollient, or from about 0.1 toabout 3 mg of film former. In some embodiments, the compositionsdisclosed herein may contain from about 0.1 to about 50 mg, from about0.1 to about 45 mg, from about 0.1 to about 40 mg, from about 0.1 toabout 35 mg, from about 0.1 to about 30 mg, from about 0.1 to about 25mg, from about 0.1 to about 20 mg, from about 0.1 to about 15 mg, fromabout 0.1 to about 10 mg, from about 0.1 to about 5 mg, from about 0.5to about 50 mg, from about 0.5 to about 45 mg, from about 0.5 to about40 mg, from about 0.5 to about 35 mg, from about 0.5 to about 30 mg,from about 0.5 to about 25 mg, from about 0.5 to about 20 mg, from about0.5 to about 15 mg, from about 0.5 to about 10 mg, from about 0.5 toabout 5 mg, from about 1.0 to about 50 mg, from about 1.0 to about 45mg, from about 1.0 to about 40 mg, from about 1.0 to about 35 mg, fromabout 1.0 to about 30 mg, from about 1.0 to about 25 mg, from about 1.0to about 20 mg, from about 1.0 to about 15 mg, from about 1.0 to about10 mg, from about 1.0 to about 5 mg, from about 2.5 to about 50 mg, fromabout 2.5 to about 45 mg, from about 2.5 to about 40 mg, from about 2.5to about 35 mg, from about 2.5 to about 30 mg, from about 2.5 to about25 mg, from about 2.5 to about 20 mg, from about 2.5 to about 15 mg,from about 2.5 to about 10 mg, and from about 2.5 to about 5 mg of filmformer. In some embodiments, the compositions disclosed herein willcontain from about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7mg, 0.8 mg, 0.9 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70mg, 80 mg, 90 mg or 100 mg of film former. In some embodiments, thecompositions disclosed herein will contain from about 0.3 mg to about0.75 mg of film former.

In some embodiments, the compositions disclosed herein further comprisesan occlusive in a concentration of about 0.01%, about 0.05%, about0.08%, about 0.1%, about 0.15%, about 0.2%, about 0.5%, about 0.8%,about 1%, about 1.3%, about 1.5%, about 1.8%, about 2%, about 2.3%,about 2.5%, about 2.8%, about 3%, about 3.5%, about 4%, about 5%, about8%, about 10%, about 13%, about 15%, about 18%, about 20%, about 23%,about 25%. In yet other embodiments, the compositions disclosed hereincomprises a range of occlusives from about 0.1% to about 25%, from about0.5% to about 20%, from about 0.5% to about 10%, from about 0.5% toabout 5%, from about 0.5% to about 3%, from about 0.75% to about 10%,from about 0.75% to about 7.5%, from about 0.75% to about 5%, from about1% to about 10%, from about 1% to about 5%, from about 1% to about 2.5%,or from about 1% to about 2%.

The compositions disclosed herein may contain from about 0.01 mg toabout 100 mg of occlusive or about 0.1 mg to about 10 mg of film former.In some embodiments, the compositions disclosed herein may contain fromabout 0.05 to about 5 mg of occlusive, or from about 0.1 to about 3 mgof occlusive. In some embodiments, the compositions disclosed herein maycontain from about 0.1 to about 50 mg, from about 0.1 to about 45 mg,from about 0.1 to about 40 mg, from about 0.1 to about 35 mg, from about0.1 to about 30 mg, from about 0.1 to about 25 mg, from about 0.1 toabout 20 mg, from about 0.1 to about 15 mg, from about 0.1 to about 10mg, from about 0.1 to about 5 mg, from about 0.5 to about 50 mg, fromabout 0.5 to about 45 mg, from about 0.5 to about 40 mg, from about 0.5to about 35 mg, from about 0.5 to about 30 mg, from about 0.5 to about25 mg, from about 0.5 to about 20 mg, from about 0.5 to about 15 mg,from about 0.5 to about 10 mg, from about 0.5 to about 5 mg, from about1.0 to about 50 mg, from about 1.0 to about 45 mg, from about 1.0 toabout 40 mg, from about 1.0 to about 35 mg, from about 1.0 to about 30mg, from about 1.0 to about 25 mg, from about 1.0 to about 20 mg, fromabout 1.0 to about 15 mg, from about 1.0 to about 10 mg, from about 1.0to about 5 mg, from about 2.5 to about 50 mg, from about 2.5 to about 45mg, from about 2.5 to about 40 mg, from about 2.5 to about 35 mg, fromabout 2.5 to about 30 mg, from about 2.5 to about 25 mg, from about 2.5to about 20 mg, from about 2.5 to about 15 mg, from about 2.5 to about10 mg, and from about 2.5 to about 5 mg of occlusive. In someembodiments, the compositions disclosed herein will contain from about0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5, mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 15.0 mg, 20 mg,25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or100 mg of occlusive. In some embodiments, the compositions disclosedherein will contain from about 0.3 mg to about 0.75 mg of occlusive.

In some embodiments, the compositions disclosed herein are administeredtwice daily, three times a day, four times a day or more. In otherembodiments, the compositions disclosed herein are administered once aday, once every other day, once every three days, once every four days,once every five days, once every six days, once a week, once every twoweeks, once a month, or less frequently. In some embodiments, thecompositions administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Thelength of the drug holiday varies between 2 days and 1 year, includingby way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days,10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days,100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days,300 days, 320 days, 350 days, and 365 days. The dose reduction during adrug holiday may be from 10%-100%, including by way of example only 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, and 100%.

Dosing Effects

In other embodiments, the compositions are administered in an amount toachieve a desired cosmetic effect. In some embodiments, the level ofpigmentation is decreased by about 5%, by about 10%, by about 12%, byabout 15%, by about 17%, by about 20%, by about 25%, by about 30%, byabout 35%, by about 40%, by about 45%, by about 45%, by about 50%, byabout 55%, by about 60%, by about 65%, by about 70%, by about 75%, byabout 80% or more. In some embodiments, the methods decrease the levelof pigmentation by about 5%, by about 10%, by about 20%, by about 30% orby about 40%. In some embodiments, the level of pigmentation isincreased by about 5%, by about 10%, by about 12%, by about 15%, byabout 17%, by about 20%, by about 25%, by about 30%, by about 35%, byabout 40%, by about 45%, by about 45%, by about 50%, by about 55%, byabout 60%, by about 65%, by about 70%, by about 75%, by about 80% ormore.

In some embodiments, an even skin tone or pigmentation is desired, forexample, in subjects afflicted with uneven pigmentation, such asvitiligo or uneven melanin distribution. In some embodiments, the levelof pigmentation is uniformly increased or decreased in localized areasto achieve an even skin tone or pigmentation distribution. In someembodiments, the level of pigmentation in localized areas is decreasedtowards a more uniform distribution of melanin or melanocytes by about1%, about 2%, about 3%, about 4%, about 5%, about 6%, by about 7%, about7%, about 8%, about 9%, by about 10%, by about 12%, by about 15%, byabout 17%, by about 20%, by about 25%, by about 30%, by about 35%, byabout 40%, by about 45%, by about 45%, by about 50%, by about 55%, byabout 60%, by about 65%, by about 70%, by about 75%, by about 80% ormore. In some embodiments, the level of pigmentation in localized areasis increased towards a more uniform distribution of melanin ormelanocytes by about 1%, about 2%, about 3%, about 4%, about 5%, about6%, by about 7%, about 7%, about 8%, about 9%, by about 10%, by about12%, by about 15%, by about 17%, by about 20%, by about 25%, by about30%, by about 35%, by about 40%, by about 45%, by about 45%, by about50%, by about 55%, by about 60%, by about 65%, by about 70%, by about75%, by about 80% or more.

In some embodiments, levels of PGF-2alpha are decreased by about 1%,about 2%, about 3%, about 4%, about 5%, about 6%, by about 7%, about 7%,about 8%, about 9%, by about 10%, by about 12%, by about 15%, by about17%, by about 20%, by about 25%, by about 30%, by about 35%, by about40%, by about 45%, by about 45%, by about 50%, by about 55%, by about60%, by about 65%, by about 70%, by about 75%, by about 80% or more.

EXAMPLES Example 1 Inhibition of Prostaglandin F2 Alpha Levels

Human keratinocytes were harvested and exposed to with UVB light toinduce PGF2 alpha release. Following exposure to UVB irradiation, thecells were treated with a composition comprising 1%4-ethoxybenzaldehyde, Indomethacin (positive control) or left untreated(negative control). After 24 hours post-treatment, PGF2 alpha levelswere measured by ELISA analysis. The composition comprising4-ethoxybenzaldehyde provided dose-dependent inhibition of PGF2 alpha inUVB-induced cells (FIG. 1).

Example 2 Skin Tone Clinical Study

Approximately 30 healthy subjects, aged 20-64 years with FitzpatrickSkin Types I-III, are enrolled in this single-center, double-blindedcomparison study. Assignments of the test product or vehicle to subjectsare randomized 2:1 to avoid bias. A total of approximately 15 subjectsreceive the test product and 15 subjects receive the vehicle. Subjectsfollow a twice-daily product application regiment for 4 weeks. No othermoisturizers, lotions or products are allowed to be applied during thestudy. At the baseline visit, subjects are graded by a dermatologist foruneven skin tone on their facial skin. Standardized digital photographsof the test site (i.e., face) are also taken. At the end of week 2,subjects are graded by a dermatologist for uneven skin tone on theirfacial skin. Standardized digital photographs of the test site (i.e.,face) are also taken. Twice-daily application of test product continuesfor another 14 days. At the end of 4 weeks, subjects are graded by adermatologist for uneven skin tone on their facial skin. Standardizeddigital photographs of the test site (i.e., face) are also taken.

Example 3 Post-Inflammatory Hyperpigmentation Clinical Study

UV irradiation stimulates a variety of biochemical pathways in the skin,resulting in free radical formation as well as the release ofinflammatory mediators. The short-term clinical effects observed fromthese pathways, include cutaneous inflammation and erythema, whilelong-term effects (for example, in the absence of treatment of theinflammatory response) result in photodamaged skin. UV irradiation mayalso cause the development of post-inflammatory hyperpigmentation sinceit induces an inflammatory response in the skin that can proceed tohyperpigmentation.

The 17 healthy female subjects, aged 26-63 years with Fitzpatrick SkinTypes III-IV, were enrolled and completed this single-center,double-blinded comparison study. At baseline, test areas were markedonto the backs of the subjects: Untreated control, 1% w 4EB composition,antioxidant product, and other test products. Assignments of the testproducts to test areas were randomized to avoid site bias. The minimalerythemal dose (MED) for each subject was also determined, using a solarsimulator with a spectral output comparable to that of natural solarradiation (UVB: 290-320 nm, UVA: 320-400 nm). Thirty micro liters ofeach test product were applied to the respective test sites by the studystaff, once daily, for 4 days. On Day 5, test sites were irradiated with1.0, 1.5, 2.0, and 2.5 MEDs. On Day 6, standardized digital photographswere taken of the test sites and test product application resumed for anadditional eleven days. Standardized digital photographs were taken ofthe test sites on Day 20. The images were analyzed using acomputer-aided colorimetry algorithm, according to the CIE colorstandard, to determine a* (redness) on Day 6 and L* (brightness) on Day20.

Both the 1% 4EB product and the antioxidant product providedstatistically significant protection from UV-induced erythema andpost-inflammatory hyperpigmentation when compared to untreated control(all P<0.01). The 1% w 4EB composition provided significantly higherprotection than the antioxidant product from UV-inducedpost-inflammatory hyperpigmentation (all P<0.0001, FIG. 2). The resultsfrom this clinical study suggest that topical 1% 4EB providessignificant protection from UV-induced post-inflammatoryhyperpigmentation when compared to the antioxidant product. The 1% w 4EBproduct provided a statistically significant reduction inhyperpigmentation (FIG. 3) and increase in skin brightness (FIG. 4) whencompared to the untreated control sample and the other test products(all P<0.0001).

Results from this clinical study suggest that topical 1% 4EB may providesignificant short-term and long-term protection from UV-inducedpost-inflammatory hyperpigmentation. The results depicted in FIG. 3 fromthe clinical study suggest that topical 1% 4EB provides a statisticallysignificant reduction in hyperpigmentation when compared to theuntreated control sample and the other test products (all P<0.0001).Additionally, as seen in FIG. 4, the 1% 4EB product provided astatistically significant increase in skin brightness when compared tothe other test products (all P<0.0001).

Example 4 Topical Formulation

A mixture (Part A) of deionized water (69.30% by weight), glycerin-USP(3.00%), Glycereth-7 (2.50%), polyacrylamide (2.25%), and ethoxydiglycol(2.20%) was heated to 80° C. A separate mixture (Part B) of glycerylstearate (5.00%), jojoba oil (3.00%), isocetyl stearate (3.25%),squalane (4.10%), cetyl ricinoleate (3.40%), 4-ethoxybenzaldehyde(1.00%), and phenoxyethanol (1.00%) was heated to 80° C. Part B wasadded to Part A with continuous mixing and stirring. The combinedmixture was cooled to 30° C. with continuous mixing to yield a cosmeticor pharmaceutical composition.

Example 5 Topical Formulation

Stearyl alcohol and a white petrolatum is melted at about 75° C. andthen a mixture of a compound of the invention, methylparaben,propylparaben, sodium lauryl sulfate, and propylene glycol weredissolved in water. The resulting mixture is stirred until it congeals.

Example 6 Topical Cream Formulation

To a commercial mineral oil-water cold cream base (100 gm) is added 0.75grams of a compound of Formula I as a fine powder or liquid withcontinuous mixing and stirring to suspend the powder in the base andyield a cosmetic or pharmaceutical composition.

Example 7 Topical Cream Formulation

A cream composition containing 1% ethoxybenzaldehyde is formulated asfollows. 1% ethoxybenzaldehyde (1% by weight), niacinamide (2% byweight), hydroquinone (2% by weight) is dissolved in propylene glycol(15 mL). The solution thus prepared is mixed with hydrophilic ointment,USP grade (85 gm) until a consistent cream is obtained.

Example 8 Topical Formulation

A therapeutic composition contain 1% ethoxybenzaldehyde and additionalactive agents is formulated as follows. Ethoxybenzaldehyde (1% byweight), niacinamide (2% by weight), and kojic acid (2% by weight) aredissolved in a mixture of ethanol (70 mL), water (10 mL) and propyleneglycol until a clear solution is obtained.

Example 9 Tablet Formulation

A compound of Formula I is mixed with dry gelatin binder and starchdiluent in a 0.1:1:1 weight ratio. A lubricating amount of magnesiumstearate is added and the mixture is formed into 210 mg tabletscontaining 10 mg of the active substituted benzaldehyde.

Example 10 Capsule Formulation

A compound of Formula I is admixed as a dry powder with a starch diluentin an approximate 0.1:2 weight ratio. The mixture is filled into 210 mgcapsules (10 mg of active compound per capsule).

Example 11 Transdermal Formulation

A compound of Formula I is admixed with a polymer matrix, a permeationenhancer and one or more other excipients. The formulation is place on abacking membrane.

Example 12 Exemplary Topical Formulation

An amount of 0.1-0.5% 4EB is admixed with 0.1-0.75% Retinol, 2.0-8.0%Niacinamide, 1.0-5.0% Tetrahexyldecyl Ascorbate, 0.001-0.5% Licoriceroot extract, 0.1-3.0% Resorcinol, and 0.1-3.0% ethyl linoleate and oneor more other excipients.

Example 13 Half-Face Study to Assess the Efficacy and Tolerance of FourTopical Products in the Treatment of Facial Hyperpigmentation

1.0 Background

Hyperpigmentation is an increase in pigmentation or color of the skinthat is abnormally dark. Hyperpigmentation occurs when an excess amountof melanin is produced. Causes of hyperpigmentation include sunexposure, certain medications, hormonal changes, PIH (post inflammatoryhyperpigmentation) or a congenital pigmentation disorder.Hyperpigmentation results in uneven skin color (tone) and a photoagedappearance. Dyspigmentation is identified as an abnormality in theformation or distribution of pigment, especially in the skin.

2.0 Purpose

This controlled clinical usage study will be conducted to evaluate andcompare the tolerance and efficacy of four topical products designed totreat facial hyperpigmentation when used by females with moderate tosevere dyspigmentation on the face.

Evaluations of efficacy will be made using clinical grading, ChromaMeter measurements, digital photography, and self-assessmentquestionnaires. Tolerance will be evaluated by clinical grading ofobjective irritation, subject assessment of subjective sensations, andmonitoring of adverse events and reactions.

3.0 Assessments

The topical treatments will produce statistically significantimprovements in clinical grading scores for efficacy parameters and havestatistically non-significant changes objective irritation assessmentsafter 12 weeks of use compared to baseline.

4.0 Study Endpoints

4.1 Primary Endpoints

Efficacy grading is conducted at baseline, week 4, week 8, and week 12.Efficacy grades is evaluated for statistical significance in: (1)changes from baseline (weeks 4, 8 and 12); and (2) comparisons to theother test products (weeks 4, 8 and 12).

Chroma Meter measurements are conducted at baseline, week 4, week 8, andweek 12. Chroma Meter measurements are evaluated for statisticalsignificance in: (1) changes from baseline (weeks 4, 8 and 12) and (2)comparisons to the other test products (weeks 4, 8 and 12).

4.2 Secondary Endpoints

Self-assessment questionnaires are conducted at baseline, week 4, week8, and week 12.

5.0 Test Material Information

5.1 Study Identification Procedures

Each study product(s) is assigned a unique test material identificationnumber (TMIN) in order to provide proper identification in records andreports.

5.2 Study Product Description(s)

Product Description Code/Formula Number Test Product #1 Base + 0.5%4EB + 0.1% Osthol Test Product #2 Base + 0.1% 4EB + 0.1% Osthol TestProduct #3 Base + 0.5% 4EB Test Product #4 Hydroquinone 4%

The base composition contains Retinol, Niacinamide, TetrahexyldecylAscorbate, Licorice root extract, Resorcinol, and ethyl linoleate and apharmaceutically/cosmetically acceptable carrier.

5.3 Method of Treatment Assignment

Subjects are numbered sequentially in the order in which they qualifyfor entry into the study.

Prior to the start of the study, the biostatistics department willgenerate a randomization list to establish treatment assignment.Subjects are assigned to use 2 of the 4 test materials according to ahalf-face design. One of the test materials is applied to the left sideof the face and another test material is applied to the right side ofthe face, as determined by the randomization design. Randomization isbased on a balanced incomplete block design with n=30 (approximately)for each treatment product.

All subjects are distributed a cleanser, moisturizer and sunscreenproduct to use throughout the study.

5.4 Instructions for Use

Sun exposure is to be avoided as much as possible. If sun exposurecannot be avoided, sunscreen SPF30 is to be re-applied to the facialskin prior to sun exposure.

It is important that the LEFT designated products are only applied onthe LEFT side of your face, and the RIGHT designated products are onlyapplied on the RIGHT side of the face.

In the morning and evening, the face is washed with the Facial Cleanserand gently patted dry.

Left Facial Side:

Using your LEFT hand, apply a thin amount of Test Product labeled LEFTonto your LEFT facial side only. Wait for product to absorb beforeapplying moisturizer.

Using your LEFT hand, apply the provided Ultra Sheer Moisturizer ontoyour LEFT facial side.

Mornings only: using your LEFT hand, apply the provided All-PhysicalSunscreen SPF30 to the LEFT side of face and throughout the day asneeded.

Right Facial Side:

Using your RIGHT hand, apply a thin amount of Base Product labeled RIGHTonto your RIGHT facial side only. Wait for product to absorb beforeapplying moisturizer.

Using your RIGHT hand, apply the provided Ultra Sheer Moisturizer ontoyour RIGHT facial side.

Mornings only: using your RIGHT hand, apply the provided All-PhysicalSunscreen SPF30 to the RIGHT side of face and throughout the day asneeded.

Avoid contact with eyes. If contact occurs, rinse thoroughly with water.If irritation or rash occurs, discontinue use and contact your doctor.

5.6 Treatment Blinding

The following procedures will be followed in order to maintain thedouble-blinded nature of this study and ensure appropriate evaluatorblinding:

The study products will be dispensed by someone other than theinvestigator or other evaluator(s). Additionally, the person in chargeof study product dispensation and the subject will be instructed not todiscuss the study products with the Investigator or other evaluator(s).

The randomization list will be secured in a locked cabinet and/orcomputer file with restricted access to a data committee consisting ofselected representatives from clinical services, quality assurance andthe statistical department.

Subjects will not be made aware of treatment assignment.

Any study product that has a label indicating its identity will becovered and labeled as Test product #1, Test product #2, Test product #3and Test product #4.

6.0 Subject

6.1 Number of Subjects

Sixty subjects meeting the eligibility requirements are expected tocomplete participation in the clinical trial. Each subject will use 2 ofthe 4 test materials, so that each test material will be used byapproximately 30 subjects.

6.2 Informed Consent Agreement

An IRB approved informed consent agreement, consistent with therequirements in 21 CFR §50.25, is given to each subject before the startof this study according to standard procedures. Subjects are ineligibleto participate in this study without a signed informed consent.

6.3 Subject Identification

Subjects are assigned a three-digit number which, when used inconjunction with the clinical study number, uniquely identifies everysubject on the study. This number remains with the subject throughoutthe study and should be used in all references to the individual in thisstudy. No number is reassigned once the study begins.

6.4 Eligibility Criteria

Individuals are admitted to study at the discretion of the Investigatoror designated, and based on medical history and findings of thepre-study interview and examination. Individuals are screened for theeligibility criteria listed below prior to study enrollment.

Inclusion Criteria: a subject is eligible to participate if they meetall of the following inclusion criteria:

1 Females, between the ages of 30 and 65 years 2 Fitzpatrick skin typeI-IV The Fitzpatrick skin classification is based on the skin'sunprotected response to the first 30 to 45 minutes of sun exposure aftera winter season without sun exposure. The categories of skin types areas follows: I. Always burns easily; never tans II. Always burns easily;tans minimally III. Burns moderately; tans gradually IV. Burnsminimally; always tans well V. Rarely burns; tans profusely VI. Neverburns; deeply pigmented 3 Presence of clinically determined moderate tosevere dyspigmentation on the face as determined by a score of 4-9 fromthe Overall Hyperpigmentation scale. 4 Willing and able to provideinformed consent and to cooperate and participate by following studyrequirements for the duration of the study and to report any adverseevent symptoms immediately 5 Good general health and free of any diseasestate or physical condition (e.g., psoriasis, moderate to severerosacea, hirsutism, scars, tattoos, etc.) which might impair evaluationsof the test sites or increase the health risk to the subject by studyparticipation. 6 Willingness to cleanse the face and remove all makeupat least 20 minutes prior to each scheduled clinic visit. No othertopical products should be applied to the face until the study visit hasbeen completed. 7 Individuals who have not used systemic retinoids(e.g., Tazorac, Soriataine, Accutane, etc.) and/or any other systemicmedication known to affect melasma at least 60 days prior to the studyentry and will not use these products throughout the duration of thestudy 8 Individuals who have not used topical retinoids and/or all othertopical medication(e.g., topical steroids, products containing benzoylperoxide, alpha- or beta-hydroxy acids, hydroquinone, and/or any otherOTC skin treatment medications) to the facial area known to affectmelasma at least 14 days prior to study entry and will not use theseproducts throughout the duration of the study. 9 Willingness to not useany other skin lightening products for the duration of the study.Subjects may continue to use regular cosmetic products (as long as theymeet inclusion criteria #7 and #8), but may not begin the use of any newfacial products other than the provided materials for the duration ofthe study. Regular use is defined as products used for a minimum of onemonth prior to enrollment without any incidence of irritation. 10 Ifsubjects are taking hormone replacement or hormones for birth control,then they must be willing not to stop or change this medication for theduration of the study. Individuals who are not taking hormones at thestart of the study must be willing not to start their use during thecourse of the study. 11 Women of childbearing potential must be willingto use a medically proven method of birth control for the duration ofthe study. 12 Willingness to avoid extended periods of sun exposure forthe duration of the study (including tanning beds), especially from 10AM to 2 PM. If brief (less than 20 minutes) periods of sun exposurecannot be avoided, then subjects are asked to use an SPF 30 product andwear protective clothing prior to and during exposure. Any extended sunexposure must be recorded on the diary. 13 Willingness to have facialexams and digital photos performed on the face.

Exclusion Criteria: a subject will not be eligible to participate ifthey meet any of the following exclusion criteria:

1 Individuals with known allergies or sensitivities to skin lighteningproducts, retinoids, hydroquinone, sulfites, moisturizers, or otherfacial products. 2 Individuals with active symptoms of allergy, activepsoriasis or eczema, sunburn, excessive scarring, tattoos, or other skincondition in the test areas that would interfere with the assessments ofthis study. 3 Individuals who are nursing, pregnant, or planning tobecome pregnant during the study. 4 Uncontrolled disease such asdiabetes, hypertension, hyper or hypo-thyroidism, active hepatitis,immune deficiency, or autoimmune disease as determined by the initialpaperwork. 5 Individuals who have a pre-existing or dormant dermatologiccondition (e.g., psoriasis, atopic dermatitis, advanced skin cancer,rosacea, acne vulgaris, atopic dermatitis, discoid lupus erythematosus,fixed drug eruption, general drug eruption, idiopathic eruptive macularpigmentation, impetigo, vitiligo, insect bites, irritant and allergiccontact and photocontact dermatitis, lichen planus, lichen simplexchronicus, morphea, pityrasis rosea, polymorphous light eruption,psoriasis, etc.) 6 Individuals who require electrolysis, waxing, or usedepilatories on the face during conduct of the study. 7 Individuals whohave had a facial peel or a laser treatment of the face within 60 daysprior to the start of the study. 8 Subjects who participated on anotherfacial usage study within the last 30 days, or who are currentlyparticipating on another usage study. 9 Subjects currently on orplanning to participate on any type of research study at anotherfacility or a doctor's office during this study.

Individuals are admitted to study at the discretion of the Investigatoror his/her designate based on medical history and findings of thepre-study interview and examination.

7.0 Study Design

7.1 Description

This controlled clinical usage study is conducted to evaluate andcompare the efficacy and tolerance (safety) of the 4 test materials inimproving the clinical signs of facial skin hyperpigmentation. The studyis conducted over the course of 12 weeks and will consist of 4 visits,at baseline, week 4, week 8, and week 12.

Women with clinically determined dyspigmentation of the facial skin arerecruited for this study. Subjects will use 2 of the 4 test materialsaccording to a half-face design, as assigned by a randomizationschedule. Test material evaluations are conducted using clinicalgrading, bioinstrumentation (Chroma Meter measurements), digitalphotography, and self-assessment questionnaires.

7.2 Outline of Procedures

Visit 1 Visit 2 Visit 3 Visit 4 Procedures: Baseline Week 4 Week 8 Week12 Qualification screening (facial exam) and eligibility paperwork XClinical evaluations on the right and left sides of the face by X X X XExpert Grader: Efficacy Parameters: overall hyperpigmentation,investigator's global assessment, global improvement ToleranceParameters: objective and subjective irritation (erythema, scaling,burning/stinging, itching, tightness, tingling) Chroma Metermeasurements on the right and left sides of the X X X X face of ahyperpigmented area Full-face Right and Left face digital images (crosspolarized X X X X and standard lighting) using VISIA CR SubjectSelf-assessment Questionnaire completed by X X X X subjects regardingvarious skin condition parameters for the right and left sides of theface

8.0 Conduct of Study

8.1 Pre-Study Procedures

Candidate subjects are screened with the eligibility requirements bytelephone prior to Visit 1.

Candidate subjects are instructed to wash their faces and remove allmakeup at least 20 minutes prior to arrival at the clinic of thebaseline visit.

Candidate subjects are assigned an appointment time for visiting theclinic.

8.2 Visit 1: Baseline

Candidate subjects are screened for qualifying criteria. Subjects thatpass the screening are assigned a screening number and graded for theremaining efficacy evaluations and tolerance (safety) evaluations asoutlined in Sections 9.1 and 9.2.

Candidate subjects will complete an Eligibility and HealthQuestionnaire, a Confidentiality Agreement and a HIPAA form. Those whopass eligibility requirements are enrolled into the study and assigned asubject number.

Those who qualify will be enrolled in the study and assigned a subjectnumber.

Subjects will have Chroma Meter measurements and digital photographyprocedures performed as described in Sections 9.3 and 9.4. Subjects willcomplete a self-assessment questionnaire as described in Section 9.5.

Subjects are distributed pre-weighed units of 2 of the test materials,according to a randomization design. One of the test materials isapplied to the right side of the face and the other test material isapplied to the left side of the face. Test material units are clearlylabeled as “Left” and “Right”. Subjects are also distributed a cleanser,moisturizer and sunscreen to use throughout the study.

Usage instructions are discussed with subjects and written usageinstructions are provided. Subjects are also provided with a calendar ofstudy visits and a daily diary to record test material application timesand comments.

8.3 Visit 2: Week 4 and Visit 3: Week 8

A clinician records concomitant medications and asks subjects if theyhave experienced any changes in their health since the last visit.

Daily diaries are collected and reviewed for compliance. Subjects thatare non-compliant are counseled that if they continue to benon-compliant they will be dropped from the study. New diaries aredistributed as needed.

Subjects participate in the following procedures: efficacy evaluationsas described in Section 9.1; tolerability evaluations described inSection 9.2; Chroma Meter measurements as described in Section 9.3; anddigital photography as described in Section 9.4. Subjects will completea self-assessment questionnaire as described in section 9.5.

8.4 Visit 4: Week 12

A clinician records concomitant medications and asks subjects if theyhave experienced any changes in their health since the last visit.

Daily diaries will be collected and reviewed for compliance.

Subjects participate in the following procedures: efficacy evaluationsas described in Section 9.1; tolerability evaluations described inSection 9.2; Chroma Meter measurements as described in Section 9.3; anddigital photography as described in Section 9.4. Subjects will completea self-assessment questionnaire and a final product evaluationquestionnaire as described in section 9.5.

9.0 Assessments

9.1 Efficacy Evaluations

At baseline, week 4, week 8, and week 12, an expert clinical graderevaluates subjects on the right and left sides of the face for thefollowing efficacy parameters using the indicated grading scales(half-points may be used for all scales below to better describe acondition):

Overall Hyperpigmentation 0 None 1 to 3 Mild 4 to 6 Moderate 7 to 9Severe

Subjects will be required to have a score of 4 to 9 for overallhyperpigmentation on both sides of the face to qualify for studyparticipation.

Investigator's Global Assessment-Hyperpigmentation:

Score Rating Description 0 Clear No brown spots or areas ofdiscoloration 1 Almost Overall there are a few brown spots withincreased clear pigmentation; they are very small in size and only veryslightly darker than surrounding skin 2 Mild Several brown spots withincreased pigmentation; they are small in size and slightly darker thansurrounding skin 3 Moderate Many brown spots with increasedpigmentation; they are medium in size and much darker than surroundingskin 4 Severe Many large brown spots with increased pigmentation; theyare large in size and markedly darker than surrounding skin

Investigator's Global Improvement Assessment:

1 Worse 2 No Improvement 3 Mildly Improved 4 Moderately Improved 5Markedly Improved

9.2 Tolerability Evaluations

At baseline, week 4, week 8, and week 12, the following tolerance/safetyparameters are scored on the right and left sides of each subject'sface:

Objective parameters (clinically graded) erythema, scaling Subjectiveparameters (assessed by subjects) burning/stinging, itching, tightness,tingling

Results of the tolerance assessments will be recorded using thefollowing scale (with half-point scores used as necessary):

0 None 1 Mild 2 Moderate 3 Severe

9.3 Chroma Meter Measurements

The Minolta Chroma Meter CR-400, in conjunction with a computer, is usedto instrumentally assess skin color. The following values are recorded:

L* Values describe the relative brightness on a gray scale from black towhite; scores increase as the skin tone becomes brighter a* Valuesdescribe the color hue ranging from red to green; scores increase withvascularization or blood flow b* Values describe the color hue rangingfrom blue to yellow; scores increase with the amount of melanin in theskin

Chroma Meter measurements are performed at baseline, week 4, week 8, andweek 12. A single measurement is taken on the right and left sides ofeach subject's face on a hyperpigmented area selected by the expertgrader. The location is recorded on a facial diagram to ensureconsistency in measurement location at each visit.

9.4 Digital Photography

Digital photography using a Nikon camera (Canfield VISIA-CR CameraSystem) is performed at baseline, week 4, week 8, and week 12, todocument visible changes in facial hyperpigmentation. For each subject,a full-face image is taken of the right and left sides of the face (2images per subject) with standard and cross-polarized lighting/filterconditions. The focus revolves around the brown channel images (derivedfrom the cross-polarized images) and the standard lighting photos.

Photos taken at weeks 4, 8 and 12 are compared to the baseline photo toensure consistent focus, lighting, placement and color. At eachphotography visit, color standards are photographed prior to beginningeach day's photography.

9.5 Self-Assessment Questionnaires

At baseline, week 4, week 8, and week 12, subjects will complete aself-assessment questionnaire regarding various skin conditionparameters on the right and left sides of the face.

10.0 Adverse Events

10.1 Definition of an Adverse Event

An adverse event (AE) is any untoward medical occurrence in a clinicalinvestigation where a subject is administered a pharmaceuticalproduct/biologic (at any dose), OTC, cosmetic product or medical deviceand which does not necessarily require a causal relationship with a testarticle. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding, for example), symptom ordisease temporally associated with the use of a medicinal productwhether or not considered related to the medicinal product. Adverseevents will be recorded on the appropriate case report forms and sourcedocuments.

10.2 Assessment of Severity and Relationship

The investigator or his medical staff will evaluate all adverse eventsas to their severity and relation to the test article. The severity ofadverse events will be graded as follows:

Mild: Awareness of a sign or symptom but easily tolerated Moderate:Discomfort sufficient to cause interference with usual activity or toaffect clinical status Severe: Incapacitating with inability to do usualactivity or to significantly affect clinical status

Assessment of Causality: the Investigator and/or trained staff memberwill also assess the relationship of any adverse event to the use of thestudy article, based upon available information, using the followingguidelines:

0 Unlikely No temporal association, or the cause of the event has beenidentified, or the test article cannot be implicated 1 Possible Temporalassociation, but other etiologies are likely to be the cause; however,involvement of the test article cannot be excluded 2 Probable Temporalassociation, other etiologies are possible, but not likely 3 DefiniteClear-cut temporal association

10.3 Definition of a Serious Adverse Event (SAE)

A serious adverse event is any experience or reaction occurring at anydose that results in any of the following outcomes: death, is lifethreatening, inpatient hospitalization or prolongation ofhospitalization, a persistent or significant disability/incapacity, or acongenital anomaly/birth defect.

Important medical events that may not result in death, belife-threatening, or require hospitalization may be considered a seriousadverse event when, based upon appropriate medical judgment, they mayjeopardize the patient or subject and may require medical or surgicalintervention to prevent one of the outcomes listed in this definition.The term “life-threatening” refers to an event in which the subject wasat risk of death at the time of event; it does not refer to an eventthat hypothetically might have caused death if it was more severe.

Hospitalization solely for the purpose of diagnostic tests, even ifrelated to an adverse event, elective hospitalization for anintervention which was already planned before the inclusion of thesubject in the study, and admission to a day-care facility may notthemselves constitute sufficient grounds to be considered as a seriousadverse event. Hospitalization is defined as being admitted to ahospital as an in-patient for greater than 24 hours.

10.4 Procedures for Reporting Adverse Events

At each visit, the subjects are questioned about adverse events using anopen question (e.g., “Have you noticed any change in your health sincethe last visit?”).

Directed questioning and examination will be performed when appropriate.All reported adverse events are documented on the appropriate formswithout omitting any requested and known information. Every time aconcomitant therapy is reported during the study, an Adverse Event Formwill be completed if appropriate and the reason for the treatment noted.

When an adverse event persists at the end of the study, the investigatorconducts a follow-up of the subject until the event is satisfactorilyresolved.

All adverse events are recorded by the Investigator onto the AdverseEvent page of the source documents describing the adverse event, onsetand stop date, severity, opinion of causality, the course of actiontaken, if any, as well as any pertinent data necessary to allow acomplete evaluation of the adverse event. For serious adverse events, anadditional report (SAE Report Form) is completed.

10.5 Procedures for Reporting Serious Adverse Events

Any serious adverse event that occurs during the study whether relatedto the treatment or not, expected or not, is reported.

10.6 Unanticipated Adverse Events

Unanticipated adverse effect is defined as any serious adverse effect onhealth or safety, any life-threatening problem or death caused by, orassociated with, the test article if that effect, problem, or death wasnot previously identified in nature, severity, or degree of incidence inthe application; or any other unanticipated serious problem associatedwith the test article that relates to the rights, safety, or welfare ofsubjects.

10.7 Anticipated Reactions

The test material when applied to the face may produce mild to moderate,transient erythema, dryness, burning, stinging and/or itching. Theresponses discussed above will not be treated as adverse reactions.These conditions may or may not resolve over time. Symptoms that arepersistent and moderate to severe in nature, or that involve elevation(e.g., edema, papules, vesicles, spreading) are considered adverseevents (AEs).

11.0 Biostatistics and Data Management

Statistical Analysis

The per protocol (PP) population is the primary population for efficacyand tolerance testing. The PP population includes all subjects who wererandomized and completed all study procedures. Clinical grading scoresand Chroma Meter measurement values at week 4, week 8, and week 12 arecompared to baseline scores/values using a paired t-test. The averagepercent change from baseline is calculated for all parameters at eachpost-baseline time point. Comparisons among the three test materials areperformed using analysis of variance (ANOVA) with paired comparisonsusing Fisher's Least Significant Difference (LSD). All differences areconsidered to be statistically significant at the p<0.05 level.

Subject Self-assessment questionnaires regarding skin conditionparameters completed by subjects at all visits are analyzed usingdescriptive statistics presenting the percentages for each question.

Data Management

Clinical grading and Chroma Meter measurements are performed usingelectronic data capture system (EDC) which documents the identity of theevaluator as well as the time and date of all entries, or all correctedentries.

The electronic data capture system (EDC) is a computerized systemdesigned for the collection of clinical data in electronic format. The 3major aspects of EDC are a graphical user interface for data entry, avalidation component to check for user data and a reporting tool foranalysis of the collected data. Statistical analyses are performed usingSAS software version 9 series (SAS Statistical Institute).

The self-assessment questionnaires are completed by subjectselectronically using HIPAA compliant Zoomerang online survey software.

Data review and analyses is performed by an independent data committee.The data committee will consist of selected representatives fromclinical services, quality assurance and the statistical department.

12.0 Results

FIGS. 7, 8 and 9 provide the results from this study. Overall, 4%hydriquinone and Base+0.5% 4EB both significantly reducedhyperpigmentation compared to baseline for every time point (See FIG.7).

FIG. 8 illustrates the overall level of hyperpigmentation as a changefrom baseline. Sites treated with 4% hydriquinone and Base+0.5% 4EBdemonstrated comparable distribution of results in individuals.

FIG. 9 provides the results of the patient self-assessmentquestionnaires. Better subject preference was observed with treatmentwith Base+0.5% 4EB than with 4% Hydroquinone.

Example 14 An Open Application Trial Evaluating the Efficacy of SixTopical Whitening Formulations to UVR Induced Tanning

1.0 Background

The following example examines acute exposure to ultraviolet radiation(UVR) stimulates melanogensis resulting in skin darkening, orhyperpigmentation.

2.0 Purpose

This study evaluates the effectiveness of six (6) test materials toreduce UV-induced tanning (hyper pigmentation) after receiving varyingdoses of UVR using a post-exposure regimen.

3.0 Assessment

The topical formulations being tested will protect human skin from theharmful effects of ultraviolet (UV) radiation compared to an untreatedsite as measured by changes in colorimetry (“L* and b*” values, ordegree of tanning according to the International Commission onIllumilation (CIE) color standard).

4.0 Endpoints

Primary Endpoint: Significant changes in L* values compared to theuntreated area

Secondary Endpoint: Significant changes in b* values compared tountreated area,

5.0 Test Material Information

5.1 Study Identification Procedures

Each study product(s) is assigned a unique test material identificationnumber (TMIN) in order to provide proper identification in records andreports.

5.2 Study Product Description(s)

Product Description Test Product #1 Base Test Product #2 Base + 1% 4EBTest Product #3 Base + 0.5% 4EB Test Product #4 Base + 1% 4EB + 0.2% DSEextract Test Product #5 Base + 1% 4EB + 0.1% Osthol Test Product #6 4%hydroquinone

The base composition contains Retinol, Niacinamide, TetrahexyldecylAscorbate, Licorice root extract, Resorcinol, and ethyl linoleate and apharmaceutically/cosmetically acceptable carrier.

5.3 Method of Treatment Assignment

Subjects are numbered sequentially in the order in which they qualifyfor entry into the study.

Prior to the start of the study, the biostatistics department generatesa randomization based on a site rotational basis to avoid skin sitebias. The irradiated, untreated site is to be included in therandomization assignment.

UV Radiation

UV radiation is supplied by an artificial source, which has a spectraloutput in the ultraviolet range comparable to that of the natural solarspectrum (UVB: 290-320 nm and UVA: 320-400 nm). The artificial lightsource used complies with the source spectral specifications asdescribed in published testing guidelines. UV irradiation is performedwith a single port solar simulator (Model 16S, Solar UV Simulator, SolarLight Co., Philadelphia) with a 150 watt xenon arc lamp. UVB+UVAradiation is obtained by using a combination of the UG-11/1 mm andWG-320 filters (Schott Glass Technologies) that are placed in theradiation path of the solar simulator.

An adjustable patient stop is used to keep the distance from solarsimulator to the radiated surface constant. At a distance ofapproximately 6.5 cm from the lamp housing, the radiated surface isexposed to a 1.0 cm diameter spot of UVA/UVB light. Exposures areperformed by varying the time of exposure (in seconds) while keeping theenergy level constant. Opening and closing of the light shutter isperformed manually. The radiation output of the xenon bulb is measuredusing the 3D-600 meter (Solar Light Co.). If a different radiometer isused for determination of radiation output, then a description of themodel and accessories is included in the report. The xenon arc lamp isignited and left on for at least 10 minutes prior to use in the study.Measurements are taken after lamp warm-up.

5.4 Product Application

Thirty (30) microliters (μl) of each test material is applied todesignated sites using an open application technique with rubbing.

One irradiated, untreated site does not receive product application.

6.0 Subject Enrollment

Number of Subjects

Fifteen (15) subjects meeting the eligibility requirements are expectedto complete participation in the clinical trial.

Informed Consent Agreement

An informed consent agreement, consistent with the requirements in 21CFR §50.25, is given to each subject before the start of this studyaccording to standard procedures.

Subject Identification

Subjects are assigned a three-digit number which, when used inconjunction with the clinical study number, uniquely identifies everysubject on the study. This number remains with the subject throughoutthe study and is used in all references to the individual in this study.No number is reassigned once the study begins.

Eligibility Criteria

Individuals are admitted to study at the discretion of an Investigatoror designated, and based on medical history and findings of thepre-study interview and examination. Individuals are screened for theeligibility criteria listed below prior to study enrollment.

Inclusion Criteria 1 Age: 18 years or older 2 Gender: Male or female 3Fitzpatrick skin type III The Fitzpatrick skin classification is basedon the unprotected response of the skin to the first 30 to 45 minutes ofsun exposure after a winter season without sun exposure. The categoriesof skin types are as follows: I. Always burns easily; never tans II.Always burns easily; tans minimally III. Burns moderately; tansgradually IV. Burns minimally; always tans well V. Rarely burns; tansprofusely VI. Never burns; deeply pigmented 4 General good health asdetermined by review of the health and eligibility questionnaire. 5Willingness to cooperate and participate by following study requirementsfor the duration of the study and to report any adverse symptomsimmediately.

Exclusion Criteria 1 Individuals with Fitzpatrick skin types I, II, IV,V and VI. 2 Individuals that have been instructed by a physician,pharmacist, or health professional to avoid sunlight because of amedical condition and/or because of drug contraindications (seeexclusion #10). 3 Individuals with known abnormal responses to sunlightor UVR light sources. 4 Individuals with a known allergy to anyingredient in a personal care product. 5 Individuals with known atopicskin diseases or neurodermatitis. 6 Women known to be pregnant, nursing,or planning to become pregnant within 6 months. 7 Individuals known tobe treated for cancer or have a history of cancer. 8 Individuals withobservable sunburn, suntan, scars, uneven tone/pigmentation, nevi orother dermal conditions on the test areas that might influence the testresults. 9 Any disease or condition that the examining Investigatordeems inappropriate for participation (e.g., uncontrolled high bloodpressure, individuals with dermal hypersensitivity requiring treatmentswith medications in exclusion #10, etc.). 10 Individuals takingmedication(s) which in the opinion of the Investigator, would interferewith the subject's participation on the study. Such medications include(but are not limited to) antihypertensive agents (hydrochorothiazide,furosemide, meticrane), ataractics (e.g., perphenazine), psychotropicagents (e.g., chlorpromazine), antihistamines (e.g., promethazinehydrochloride), oral hypoglycemic agents (e.g., tolubutamide,chlorpropamide), and tetracycline antibiotics (e.g.,dimethylchloroteteacycline, tetracycline).

Individuals are admitted to the study at the discretion of theInvestigators based on medical history and findings of the pre-studyinterview and examination. Each subject is expected to complete the fullcourse of the study.

7.0 Study Design

Description

This open application clinical study is conducted to evaluate theeffectiveness of six (6) test materials to suppress the development ofskin pigmentation after receiving varying doses of UVR using apre-exposure/post-exposure regimen. Procedures are conducted as outlinedin the table of procedures.

Outline of Procedures

Visits 3, 7, 10, 13, 15, Visits 18, 21, 24, 27 3-26 Off Days 8, 12, 16,Days 8-13, Visit 1 Visit 2 Days 3-7, 14, 19, 22, 25, 29, 15-20, 22-27,Visit 27 Day 1 Day 2 21, 28 and 35 32, 36 29-34 Day 36 Paperwork and XScreening MED X Determination Grade MED X 1.0, 1.5, 2.0 and 2.5 X MEDExposure Test Material X Application Chromameter X* X Photography X* X*Photography and Chromameter is done prior to test material application.

8.0 Conduct of Study

8.1 Visit 1: Baseline: Day 1

Individuals are given an informed consent (IC) document to read. Theyhave all of their study related questions answered by the Investigatoror his/her designated staff and if they agree, they sign two copies ofthe IC.

Subjects complete a health and eligibility questionnaire, aconfidentiality agreement-photographic release form, and a HIPAA releaseform.

The Investigator or his/her designated staff examine the back (test sitearea) for evenness of skin tone (Fitzpatrick skin type III only) and toensure the lack of uneven suntan, sunburn, scars, birthmarks, moles,vitiligo, keloids, skin abnormalities, or any other dermal markings.

Eligible individuals are enrolled into the study and assigned a subjectnumber.

Subjects receive 5-7 irradiation exposures expressed as J/sq cm(adjusted to the erythema action spectrum) on adjacent unprotected skinsites on the lower back. Each exposure represents a 25% increase inenergy over the previous exposure.

Seven (7) 3.0 cm×5.0 cm areas are marked on the lower back.

8.2 Visit 2: Day 2

1. Test sites from Visit 1 are examined using either a tungsten or warmwhite fluorescent light that provides 450 to 550 lux of illumination.

2. Sites are scored for erythema using the scale outlined in section 9.1for MED Determination.

3. Using the determined MED value, UVR exposures are calculated. Theamount of UVR delivered to each subject's test sites depends on thisvalue.

4. Each area is exposed to UVR in doses of 1.0×, 1.5× and 2.0× and 2.5×the previously determined MED.

5. Subjects have a rest period of 5 days while tanning develops at theirradiated sites. Subjects resume study procedures on Day 8.

8.3 Visits 3, 7, 10, 13, 15, 18, 21 & 24: Days 8, 12, 16, 19, 22, 25, 29& 32

Digital photography will be conducted as outlined in section 9.3

Chromameter measurements will be conducted as outlined in section 9.2

Test Materials are applied as outlined in Section 5.4. A seventh siteserves as an irradiated untreated control.

8.4 Visits 4-6, 8, 9, 11, 12, 14, 16, 17, 19, 20, 22, 23, 25 & 26: Days9-11, 13, 15, 17, 18, 20, 23, 24, 26, 27, 30, 31, 33 & 34

Test Materials will be applied as outlined in Section 5.4. A seventhsite will serve as an irradiated untreated control.

8.5 Visit 27: Day 36

Digital photography are conducted as outlined in section 9.3 andchromameter measurements are conducted as outlined in section 9.2

9.0 Assessments 9.1 MED Determination Scoring

− no visible erythema ? questionable response; unclear + erythema,extending to the borders ++ erythema, with or without edema present

The site receiving the lowest dose of combined UV that produced mildredness reaching the borders of the site will receive a score of +, andwill be recorded as the MED (US) for that subject.

Each subject's MED may be different, but will likely be approximately 70mJ/cm2. The intensity of UVR delivered to each subject's test sitesdepends on this value.

9.2 Chromameter Measurements

The Minolta Chroma Meter CR-400, in conjunction with a computer, is usedto assess skin color. L* values describe the relative brightness on agray scale from black to white, and scores increase as the skin tonebecomes brighter/lighter. b* values describe the color hue ranging fromblue to yellow and scores increase with the amount of melanin in theskin. One measurement is taken at each of the six treated sites and theuntreated irradiated control site.

9.3 Imaging Procedures

Digital photography is performed on the six treated sites and theuntreated irradiated control site using a Nikon D300 camera and MicroNikkor lens. Test and control sites are clearly labeled for eachindividual, and color standards are visible in each subject'sphotograph. Images are saved as raw data (NEF files) and also as JPEGfiles, arranged by subject. Photographs are analyzed for colorimetryusing Image Pro Analysis software.

10.0 Adverse Events

10.1 Definition of an Adverse Event

An adverse event (AE) is any untoward medical occurrence in a clinicalinvestigation where a subject is administered a pharmaceuticalproduct/biologic (at any dose), OTC, cosmetic product or medical deviceand which does not necessarily require a causal relationship with a testarticle. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding, for example), symptom ordisease temporally associated with the use of a medicinal productwhether or not considered related to the medicinal product.

10.2 Assessment of Severity and Relationship

The investigator or his/her medical staff evaluates all adverse eventsas to their severity and relation to the test article. The severity ofadverse events is graded as follows:

Mild Awareness of a sign or symptom but easily tolerated ModerateDiscomfort sufficient to cause interference with usual activity or toaffect clinical status Severe Incapacitating with inability to do usualactivity or to significantly affect clinical status

The Investigator and/or trained staff member also assesses therelationship of any adverse event to the use of the study article, basedupon available information, using the following guidelines:

0 Unlikely No temporal association, or the cause of the event has beenidentified, or the test article cannot be implicated 1 Possible Temporalassociation, but other etiologies are likely to be the cause; however,involvement of the test article cannot be excluded 2 Probable Temporalassociation, other etiologies are possible, but not likely 3 DefiniteClear-cut temporal association

10.3 Definition of a Serious Adverse Event (SAE)

A serious adverse event is any experience or reaction occurring at anydose that results in any of the following outcomes: death; is lifethreatening; inpatient hospitalization or prolongation ofhospitalization; a persistent or significant disability/incapacity; or acongenital anomaly/birth defect.

Important medical events that may not result in death, belife-threatening, or require hospitalization may be considered a seriousadverse event when, based upon appropriate medical judgment, they mayjeopardize the patient or subject and may require medical or surgicalintervention to prevent one of the outcomes listed in this definition.The term “life-threatening” refers to an event in which the subject wasat risk of death at the time of event; it does not refer to an eventthat hypothetically might have caused death if it was more severe.

Hospitalization solely for the purpose of diagnostic tests, even ifrelated to an adverse event, elective hospitalization for anintervention which was already planned before the inclusion of thesubject in the study, and admission to a day-care facility may notthemselves constitute sufficient grounds to be considered as a seriousadverse event. Hospitalization is defined as being admitted to ahospital as an in-patient for greater than 24 hours.

10.4 Procedures for Reporting Adverse Events

At each visit, the subject is questioned about adverse events using anopen question (e.g., “Have you noticed any change in your health sincethe last visit?”).

Directed questioning and examination is performed when appropriate. Allreported adverse events are documented on the appropriate forms withoutomitting any requested and known information.

Every time a concomitant therapy is reported during the study, anAdverse Event Form is completed if appropriate and the reason for thetreatment noted.

When an adverse event persists at the end of the study, follow-up of thesubject is conducted until the event is satisfactorily resolved.

10.5 Unanticipated Adverse Events

Unanticipated adverse effect is defined as any serious adverse effect onhealth or safety, any life-threatening problem or death caused by, orassociated with, the test article if that effect, problem, or death wasnot previously identified in nature, severity, or degree of incidence inthe application; or any other unanticipated serious problem associatedwith the test article that relates to the rights, safety, or welfare ofsubjects.

10.6 Anticipated Reactions

The test material when applied to the skin may produce mild irritationsuch as erythema, tanning, scaling/dryness, burning and/or stinging atthe test site or surrounding the test sites. The responses discussedabove will not be treated as adverse reactions. If sites begin to showmild levels of erythema, then product applications may be skipped asneeded in order to avoid redness, which would interfere in theassessment of product efficacy. The UV exposure will create sunburn andpossible discomfort. Hypo- or hyperpigmentation may occur at the skinsites, and the skin may show irritation where test material or vehicleis applied. These conditions may or may not resolve over time. Symptomsthat are persistent and moderate to severe in nature, or that involveelevation (e.g., edema, papules, vesicles, spreading) will be consideredadverse events (AEs).

11.0 Biostatistics and Data Management

Digital photographs will be taken of the entire treatment and controlareas under standardized conditions. Images will be analyzed via acomputer-aided colorimetry algorithm to determine L* values and b*values. The L* values of the treated areas and untreated areas from theimages and Chromameter measurements will be compared to provide a “SkinLightening Factor.”

The “L*and b’ colorimeter values are expected to be different betweenthe test material-treated and untreated, irradiated area. Since eachpatient will serve as his own control, p-values will be determined bythe two-tailed Student t-test.

APPENDIX 2 Exemplary Study Calendar

SUNDAY MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY 17 18 19 20 2122 23 V1/D1 V2/D2 D3 D4 D5 D6 10:00-12:00 10:00-1:00 OFF OFF OFF OFF4:30-6:00 4:00-6:00 Paperwork Irradiation MED 24 25 26 27 28 29 30 D7V3/D8 V4/D9 V5/D10 V6/D11 V7/D12 V8/D13 OFF 11:00-1:00 11:30-12:3011:30-12:30 11:30-12:30 11:00-1:00 10:00-12:00 4:30-6:00 5:00-6:005:00-6:00 5:00-6:00 4:30-6:00 Product App Photos Product App Product AppProduct App Photos Chromameter Chromameter Product App Product App 1 2 34 5 6 7 D14 V9/D15 V10/D16 V11/D17 11:30-12:30 V12/D18 11:30-12:30V13/D19 V14/D20 OFF 11:30-12:30 11:00-1:00 5:00-6:00 5:00-6:0011:00-1:00 10:00-12:00 5:00-6:00 4:30-6:00 Product Product App 4:30-6:00Product App Product App Photos App Photos Chromameter ChromameterProduct App Product App 8 9 10 11 12 13 14 D21 V15/D22 V16/D23 V17/D24V18/D25 V19/D26 V20/D27 OFF 11:00-1:00 11:30-12:30 11:30-12:3011:00-1:00 11:30-12:30 10:00-12:00 4:30-6:00 5:00-6:00 5:00-6:004:30-6:00 5:00-6:00 Product App Photos Product App Product App PhotosProduct App Chromameter Chromameter Product App Product App 15 16 17 1819 20 21 D28 OFF V21/D29 V22/D30 V23/D31 V24/D32 V25/D33 V26/D3411:00-1:00 11:30-12:30 11:30-12:30 11:00-1:00 4:30-6:00 11:30-12:3010:00-12:00 4:30-6:00 5:00-6:00 5:00-6:00 Photos 5:00-6:00 Product AppPhotos Product App Product App Chromameter Product App ChromameterProduct App Product App 22 23 24 25 26 27 28 D35 V27/D36 OFF 11:00-1:004:30-6:00 Photos Chromameter

12.0 Results

An increase in brightness of UV-induced pigmentation was observed inpatient sites treated with Base+0.5% 4EB compared to 4% hydroquinone(See FIG. 6).

Example 15 MelanoDerm Model

The following example provides a validated model for melanin productionusing human skin equivalent.

Melanogenesis study: The melanoderm tissues (MEL-300B) were obtainedfrom MatTek Corporation and cultured for 14 days at specifiedconditions. The tissues were treated with 15 μl of formulations or with25 μl of positive (1% Kojic acid solution) and negative (DI water)controls every other day during this period. Tissues were taken out inbetween this period at specific days and fixed for histological imaging,light microscopy or for melanin quantification.

As seen in FIG. 6, Base+1% 4EB was more effective than Kojic Acid inreducing the melanin content of the skin equivalent.

While preferred embodiments have been shown and described herein, itwill be obvious to those skilled in the art that such embodiments areprovided by way of example only. Numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from the embodiments. It should be understood that variousalternatives to the embodiments described herein may be employed inpracticing the embodiments. It is intended that the following claimsdefine the scope of the embodiments and that methods and structureswithin the scope of these claims and their equivalents be coveredthereby.

What is claimed:
 1. A method of treating hyperpigmentation or ahypermelanosis disorder in an individual, comprising administering tothe individual in need thereof an effective amount of a compositioncomprising: from about 0.01% to about 2% substituted benzaldehyde,wherein the substituted benzaldehyde is 2-ethoxybenzaldehyde,4-ethoxybenzaldehyde, 4-allyloxybenzaldehyde or 4-propoxybenzaldehyde,and a pharmaceutically or cosmetically acceptable carrier.
 2. The methodof claim 1, further comprising administering to the individual in needthereof an effective amount of from about 0.01% to about 5.0% of anadditional agent, wherein the additional agent is selected from thegroup consisting of Retinol, Niacinamide, Tetrahexyldecyl Ascorbate,Glycyrrhiza Glabra (Licorice) Root Extract, Hexyl Resorcinol, ethyllinoleate, or mixtures thereof.
 3. The method claim 1, wherein theamount of substituted benzaldehyde in the composition is about 0.5%. 4.The method of claim 1, wherein the method reduces melanin distributionby about 10% to about 40%.
 5. The method of claim 1, wherein thecomposition is topically or transdermally administered to the skin ofthe individual.
 6. The method of claim 1, wherein the compositionfurther comprises one or more additional active agents.
 7. The method ofclaim 6, wherein the additional active agent is an antioxidant, asunscreen, a sunprotectant, a sunblock, a skin-lightening agent, ananti-inflammatory agent, an anti-acne agent or mixtures thereof.